PARP Inhibitor Therapy for Prostate Cancer Patients: Emerging Combinations

Introduction

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are drugs that prevent the repair of DNA single-stranded breaks and promote their conversion to double-stranded breaks resulting in a synthetic lethality.1 These drugs have demonstrated promising results for the treatment of metastatic castrate-resistant prostate cancer (mCRPC) patients who experience disease progression following prior androgen receptor pathway inhibitor (ARPI) and/or taxane-based chemotherapy.

There is growing interest in combining these agents with other classes of drugs that may have synergistic mechanisms of action. A prime example of this is the use of combination PARP inhibitors and APRIs, with ARPIs inhibiting the transcription of specific homologous recombination repair (HRR) genes, inducing an HRR deficiency-like state, which potentiates PARP inhibitor activity, and, conversely, PARP inhibitors upregulating androgen receptor signaling, enhancing ARPI activity.2-4 This has culminated in the approval of three PARP inhibitor/ARPI combinations by the US Food and Drug Administration (FDA) for the treatment of mCRPC patients in the first line setting:
  • Olaparib plus abiraterone for BRCA1/2-mutated patients5
  • Niraparib plus abiraterone for BRCA1/2-mutated patients6
  • Talazoparib plus enzalutamide for HRR-mutated patients7
Numerous other PARP inhibitor combination strategies have since been evaluated, although, to date, none have resulted in regulatory approval for use in clinical practice. In this Center of Excellence article, we discuss emerging and potentially important PARP inhibitor combination strategies.

PARP Inhibitors + Radium-223

Olaparib + Radium-223

For patients with bone metastases, it has been theorized that the combination of a PARP inhibitor and radium-223 may have synergistic mechanisms of action. PARP inhibitors have shown efficacy as radiosensitizing agents which may promote the efficacy of radium-223, an α-emitting radioisotope that induces DNA double-strand breaks leading to cell death. This formed the foundation for the COMRADE trial, an open-label, multi-center, phase 1/2 study trial to test the safety and efficacy of radium-223 and olaparib. This trial included men with mCRPC who had ≥2 bone metastases without evidence of concurrent visceral metastases or lymphadenopathy > 4 cm.

The phase 1 portion of the study employed a 3+3 dose escalation design with fixed-dose radium-223 (55 kBq/kg IV every 4 weeks x 6) and escalating doses of olaparib. The dose level 1 (DL1) for was olaparib 200 mg PO BID while DL2 was 300 mg PO BID. In phase 1, the primary objective was to determine the recommended phase 2 dose (RP2D) for the randomized portion of the study, which was found to be 200 mg BID for olaparib. No dose limiting toxicities were observed at either DL1 or DL2. However, 5 of 6 patients enrolled at DL2 required dose reduction. Assessing secondary objectives, the authors found that the PSA response and alkaline phosphatase response rates were 16.7% (n=2) and 67% (n=8), respectively. At a median follow-up of 6.5 months, the 6 months rPFS was 58%, and the 12 months OS was 56%. Based on these results, the investigators concluded that olaparib can be safely combined with radium-223 at the RP2D of 200 mg orally twice daily with fixed dose radium-223.8

Niraparib + Radium-223

Utilizing a similar treatment strategy to that seen in the COMRADE trial, the combination of niraparib and radium-223 was evaluated in the phase 1b trial, NiraRad. This trial included 30 men with progressive mCRPC following ≥1 line of an ARPI and had evidence of bone metastases without bulky visceral disease and no documented BRCA1/2 alterations. The niraparib dose was escalated in combination with standard dosing of Radium-223 using a time-to-event continual reassessment method. The investigators determined that for patients with prior chemotherapy exposure, the maximum tolerated dose (MTD) for niraparib was 100 mg, whereas the MTD for chemotherapy-naïve patients was 200 mg. The median rPFS for all patients included in analysis was 7.1 months with an estimated 6-month rPFS of 51%.9

PARP Inhibitors + 177Lu-PSMA-617


177Lu-PSMA-617 delivers significant beta radiation to PSMA-expressing tumors causing single strand DNA breaks, which are typically repaired by PARP-dependent pathways. Blocking the PARP enzyme could have a synergistic mechanism of action by converting DNA single strand breaks to lethal double strand breaks via replication fork collapse. In the LuPARP trial presented at ASCO 2023, the investigators hypothesized that olaparib would promote the radiosensitization of 177Lu-PSMA-617, resulting in intensification of DNA damage and, thus, improved efficacy.

The LuPARP phase 1 trial schema was as follows:

figure-1-PARPi-emerging2x.jpg

This trial included 48 patients with mCRPC, and all eligible patients had received a prior ARPI and docetaxel. All patients underwent a 68Ga-PSMA-11 plus an FDG-PET/CT with the following inclusion criteria:
  • PSMA SUVmax >15 at any site
  • SUVmax >10 at other sites
  • No FDG discordance
This study followed a 3+3 dose escalation design. In cohorts 1-6, the dose of olaparib was sequentially increased from 50 mg to 300 mg on days 2–15 (day 0: day of LuPSMA administration). In cohorts, 7 to 9, the timing of olaparib administration (days -4 to 14 and -4 to 18), along with the dose of olaparib, were sequentially varied. The investigators determined that the recommended phase 2 dose was 7.4 Gb of 177Lu-PSMA-617 in conjunction with olaparib 300 mg twice daily on days -4 to 18 of each 6-weekly cycle. 177Lu-PSMA-617 in combination with olaparib was well-tolerated, with no dose limiting toxicities. One treatment-related serious AE occurred (febrile neutropenia). Dose delay due to hematological toxicity occurred in 3 (9%) patients (cohorts 2, 5, and 6). Dose reduction was required in 4 patients (12%), including 3 due to hematological toxicity and 1 due to xerostomia.

From an efficacy standpoint, 177Lu-PSMA-617 in combination with olaparib demonstrated promising activity: in the overall cohort (i.e., Cohorts 1 to 9), the PSA50 and PSA90 response rates were 66% and 44%, respectively. The objective response rate (ORR) by RECIST v1.1 criteria was 78%.10 Compared to the results of the TheraP and VISION trials, the PSA50 responses were identical to those from TheraP (66%) and higher than those in VISION (46%).11,12 The PSA90 response of 44% in LuPARP was slightly higher than that in TheraP (38%).

Moreover, early results from Cohorts 7-9 were promising with PSA50 and PSA90 responses of 75% and 58%, respectively. However, results from this Phase 1 trial are not designed, nor powered, to assess efficacy outcomes.

figure-2-PARPi-emerging2x.jpg

PARP Inhibitors + Immune Checkpoint Inhibitors

While immunotherapy has shown limited success in the mCRPC disease space, it is hypothesized that the increased cellular DNA damage induced by PARP inhibitors may lead to increased immune priming and subsequently promote immune cell infiltration. This has served as the rationale for emerging trials of combination PARP inhibitors and immune checkpoint inhibitors.

Rucaparib + Nivolumab

The CheckMate 9KD trial has evaluated the combination of rucaparib and nivolumab in two cohorts:
  • Cohort A1: Post-chemotherapy mCRPC (1–2 taxanes and ≤2 ARPIs)
  • Cohort A2: Chemotherapy-naïve mCRPC (Received prior ARPI)
In this phase II trial, patients received nivolumab 480 mg every 4 weeks plus rucaparib 600 mg two times per day until disease progression or unacceptable toxicity. The co-primary endpoints were ORR and PSA50 response rates in both all-treated patients and patients with homologous recombination deficiency (HRD)-positive tumors.

Among patients in Cohort A1 (n=58), the ORR was 10.3% in the overall cohort. Superior ORRs were observed in the HRD-positive (17.2%) and BRCA1/2-positive tumors (33.3%). PSA50 responses were observed in 12% of patients in the overall cohort, compared to 18% and 42% of HRD-positive and BRCA1/2-positive tumors, respectively. Median rPFS ranged between 4.9 and 5.8 months, whereas OS ranged between 13.9 and 15.4 months.

figure-3-PARPi-emerging2x.jpg

As expected, response rates and survival outcomes were superior in the less heavily pre-treated Cohort A2 (n=39). The ORR was 15.4% in the overall cohort, with ORRs of 25% and 33.3% in the HRD-positive and BRCA1/2-positive tumors, respectively. PSA50 responses were observed in 27.3% of patients in the overall cohort, compared to 42% and 85% of HRD-positive and BRCA1/2-positive tumors, respectively. Median rPFS ranged between 8.1 and 10.9 months, whereas OS ranged between 20.2 and 22.7 months.

figure-4-PARPi-emerging2x.jpg

In cohorts A1 and A2, respectively, the most common any-grade and grade 3–4 treatment-related adverse events were nausea (41%) and anemia (14–21%). Approximately 25% of patients discontinued treatment secondary to adverse events.13

Olaparib + Pembrolizumab

Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 months of screening. In this trial, 102 patients received pembrolizumab 200 mg IV every 3 weeks + olaparib 400 mg capsule or 300 mg tablet orally twice daily. Patients could have received one chemotherapy agent other than docetaxel for mCRPC and ≤2 ARPIs. The primary endpoints were PSA50 response rates, ORR, and safety.

A PSA50 response was observed in 15% of patients. The confirmed ORR was 8.5% (5 partial responses) among patients with measurable disease.

figure-5-PARPi-emerging2x.jpg

The median rPFS was 4.5 months, and the median OS was 14 months. Treatment-related adverse events were observed in 91% of patients. Grade 3–5 events occurred in 48% of patients (6% deaths), most commonly anemia (27%), fatigue (6%), and neutropenia (5%).14

This combination of olaparib + pembrolizumab was next assessed in the open-label, phase III KEYLYNK-010 trial that randomized mCRPC patients that had progressed on one prior ARPI and docetaxel in a 2:1 fashion to olaparib + pembrolizumab versus the alternate ARPI (i.e., if had received abiraterone, given enzalutamide and vice versa). The dual primary endpoints were rPFS and OS. This trial included 793 patients of whom 529 and 264 were randomized to olaparib + pembrolizumab and an alternate ARPI, respectively. There was no significant difference in rPFS (median: 4.4 versus 4.2 months; HR: 1.02, 95% CI: 0.82 – 1.25, p=0.55) or OS between the two treatment arms (median 15.8 versus 14.6 months; HR: 0.94, 95% CI: 0.77 – 1.14, p=0.26).

figure-6-PARPi-emerging2x.jpg

Grade 3 treatment-related adverse events were more common with olaparib + pembrolizumab (35% versus 9%), with events leading to treatment discontinuation occurring in 11% and 1.6% of patients in the intervention and control arms, respectively. The most common grade ≥3 adverse events with olaparib + pembrolizumab were anemia (20%), fatigue (3%), and asthenia (2.3%).15

Olaparib + Durvalumab

In a single arm phase II trial, the combination of durvalumab 1,500 mg IV every 4 weeks and olaparib 300 mg twice daily was evaluated in 17 mCRPC patients with disease progression following prior ARPI. Overall, 9/17 (53%) patients had a PSA50 response, with 4 of these 9 patients having a radiographic response. The median rPFS of patients with DDR gene alteration was 16.1 months, with a 12-months PFS probability of 83.3%, compared to 36.4% in those without mutations (p=0.031). The most common treatment-related grade 3 or 4 adverse events were anemia (24%), lymphopenia (12%), infection (12%), and nausea (12%).16

figure-7-PARPi-emerging2x.jpg

Talazoparib + Avelumab

The JAVELIN PARP Medley trial is a phase 1b/2 basket trial evaluating the combination of talazoparib and avelumab in patients with advanced solid tumors, including mCRPC patients with and without HHR alterations (n=21). Patients received avelumab 800 mg every 2 weeks plus talazoparib 1mg once daily. In the overall cohort, PSA responses were observed in 2/21 patients, and in the HRR positive mCRPC cohort, the ORR was 11.1%.17

PARP Inhibitors + Bipolar Androgen Therapy

Prostate cancer cells can develop resistance to androgen ablation through an adaptive marked upregulation of androgen receptors over time in response to a low-androgen milieu. This upregulation can make these cells vulnerable to supraphysiologic testosterone exposure. Bipolar Androgen Therapy (BAT) has been proposed as a technique to overcome AR therapeutic resistance. Rapid cycling between polar extremes of supraphysiologic and near-castrate serum testosterone in asymptomatic men with mCRPC has proven to be safe and effective.18

Supraphysiologic androgen levels have been shown to induce double-strand DNA breaks and suppress the expression of genes involved in the DNA repair process.19,20 This has served as the rationale for evaluating the combination of olaparib and BAT in a single arm phase II trial. Thirty-six patients with mCRPC and disease progression following abiraterone and/or enzalutamide received olaparib 300 mg twice daily plus BAT (testosterone cypionate/enanthate 400 mg every 28 days with ongoing androgen deprivation). A PSA50 response was observed in 11/36 patients (31%) at 12 weeks, and the median rPFS in the intent-to-treat cohort was 13 months. The most frequently observed treatment-related adverse events were gastrointestinal related and fatigue. Five patients had grade ≥3 treatment-related adverse events, including one stroke (Grade 4) and one myocardial infarction (Grade 5).21

figure-8-PARPi-emerging2x.jpg

PARP Inhibitors + Chemotherapy

The combination of the low dose oral PARP inhibitor veliparib (ABT-888) and temozolomide for docetaxel pre-treated mCRPC patients was evaluated in a single-arm, open-label, pilot study published by Hussain et al. in 2014. This trial included 26 patients with a median baseline PSA of 170 ng/ml. A PSA response was observed in 2 patients (8%), with a further 13 having stable PSA levels. The median PFS was 9 weeks, and the median OS was 40 weeks. Grade 3/4 adverse events occurred in >10 % of patients include thrombocytopenia (23 %) and anemia (15 %).22

PARP Inhibitors + Targeted Therapies

Olaparib + Cediranib

Cediranib is a pan-vascular endothelial growth factor receptor inhibitor that suppresses the expression of HRR genes and increases sensitivity to PARP inhibition in preclinical models.23 In an open-label phase II trial, patients with progressive mCRPC were randomly assigned to receive either cediranib 30 mg once daily plus olaparib 200 mg twice daily versus olaparib 300 mg twice daily alone. In the intention-to-treat cohort of 90 patients, the median rPFS was 8.5 months in the combination arm versus 4 months in the PARP inhibitor monotherapy arm (HR 0.62; 95% CI: 0.39–0.97, p=0.036). Among patients with HRR-deficient mCRPC, the median rPFS was 10.6 months with combination treatment versus 3.8 months with olaparib monotherapy. In the subset of patients with BRCA2-mutated mCRPC, median rPFS was 13.8 months in the combination arm versus 11.3 months in the olaparib only arm. Grade 3–4 adverse events occurred in 61% of patients in the combination arm, compared to 18% of patients in the monotherapy arm.24

figure-9-PARPi-emerging2x_2.jpg

Olaparib + Ceralasterib

In an in vitro study, the combination of olaparib and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor, ceralasterib, was shown to selectively cause cell death in ATM-deficient cells.25 This served as the basis for the TRAP trial, a two-cohort study of mCRPC patients with HRR mutations (BRCA1/2 or ATM; n=35) and another without HRR mutations (n=12). All patients had progressed on ≥1 prior mCRPC therapy with no prior PARP inhibitors or platinum chemotherapy. In this study, olaparib was administered twice daily at a standard dose, and ceralasterib was administered daily on days 1¬–7 of a 28-day cycle. The primary endpoint was disease response (confirmed PSA50 or RECIST response). The response rate in the HRR cohort was 33%, compared to 11% in the HRR negative cohort, including 21% of patients experiencing a grade 3 treatment-related adverse event (no grade 4–5 events).26

figure-10-PARPi-emerging2x.jpg

Conclusions and Future Trials


PARP inhibitors are an exciting class of drugs with a unique mechanism of action that lends itself to potential synergistic combinations with other classes of drugs. To date, the only combination to receive regulatory approval is that of PARP inhibitors + ARPIs; however, numerous exciting combinations continue to emerge. Additionally, given their success in the mCRPC disease space, there is increased interest in evaluating such combinations in earlier disease stages, including the high-risk localized and the metastatic hormone-sensitive settings. Summarized in the table below are select trials of PARP inhibitor combination therapy across the prostate cancer spectrum.

table-1-PARPi-emerging2x.jpg

Published March 2024

Written by: Zachary Klaassen, MD, MSc Associate Professor of Urology Urologic Oncologist Medical College of Georgia, Georgia Cancer Center Augusta, GA and Rashid Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, Ontario, Canada
References:
  1. Xie T, Dickson K, Yee C, et al. Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival. Cancers (Basel). 2022;14(19):4621.
  2. Asim M, Tarish F, Zecchini HI, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun. 2017; 8:374.
  3. Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012; 2:1134-49.
  4. Li L, Karanika S, Yang G, et al. Androgen receptor inhibitor-induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer. Sci Signal. 2017;10: eaam7479.
  5. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration. Accessed on March 10, 2024.
  6. FDA approves niraparib and abiraterone acetate plus prednisone for BRCA-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-and-abiraterone-acetate-plus-prednisone-brca-mutated-metastatic-castration. Accessed on March 10, 2024.FDA approves niraparib and abiraterone acetate plus prednisone for BRCA-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-and-abiraterone-acetate-plus-prednisone-brca-mutated-metastatic-castration. Accessed on March 10, 2024.FDA approves niraparib and abiraterone acetate plus prednisone for BRCA-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-and-abiraterone-acetate-plus-prednisone-brca-mutated-metastatic-castration. Accessed on March 10, 2024.
  7. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate. Accessed on March 10, 2024.FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate. Accessed on March 10, 2024.FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate. Accessed on March 10, 2024.
  8. Pan E, Xie W, Ajmera A, et al. A Phase I Study of Combination Olaparib and Radium-223 in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Bone Metastases (COMRADE). Mol Cancer Ther. 2023;22(4):511-518.
  9. Quinn Z, Leiby B, Sopavde G, et al. Phase I Study of Niraparib in Combination with Radium-223 for the Treatment of Metastatic Castrate-Resistant Prostate Cancer. Clin Cancer Res. 2023;29(1):50-59.
  10. Sandhu S, Joshua AM, Emmett L, et al . LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(16):Suppl 5005.
  11. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385:1901-1103
  12. Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.
  13. Fizazi K, Retz M, Petrylak DP, et al. Nivolumab plus rucaparib for metastatic castration-resistant prostate cancer: results from the phase 2 CheckMate 9KD trial. J Immunother Cancer. 2022;10(8):e004761.
  14. Yu EY, Piulats JM, Gravis G, et al. Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study. Eur Urol. 2023;83(1):15-26.
  15. Antonarakis ES, Park SH, Goh JC, et al. Pembrolizumab Plus Olaparib for Patients With Previously Treated and Biomarker-Unselected Metastatic Castration-Resistant Prostate Cancer: The Randomized, Open-Label, Phase III KEYLYNK-010 Trial. J Clin Oncol. 2023;41(22):3839-3850.
  16. Karzai F, VanderWeele D, Madan RA, et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer. 2018;5(1):141.
  17. Yap TA, Bardia A, Dvorkin M, et al. Avelumab Plus Talazoparib in Patients With Advanced Solid Tumors: The JAVELIN PARP Medley Nonrandomized Controlled Trial. JAMA Oncol. 2023;9(1):40-50.
  18. Denmeade SR, Wang H, Agarwal N, et al. TRANSFORMER: A Randomized Phase II Study Comparing Bipolar Androgen Therapy Versus Enzalutamide in Asymptomatic Men With Castration-Resistant Metastatic Prostate Cancer. J Clin Oncol. 2021;39(12):1371-1382.
  19. Haffner MC, Aryee MJ, Toubaji A, et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat Genet. 2010;42(8):668-675.
  20. Chatterjee P, Schweizer MT, Lucas JM, et al. Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage. J Clin Invest. 2019;129(1):4245-4260.
  21. Schweizer MT, Gulati R, Yezefski T, et al. Bipolar androgen therapy plus olaparib in men with metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2023;26(1):194-200.
  22. Hussain M, Carducci MA, Slovin S, et al. Targeting DNA repair with combination veliparib (ABT-888) and temozolomide in patients with metastatic castration-resistant prostate cancer. Invest New Drugs. 2014;32(5):904-912.
  23. Kaplan AR, Gueble SE, Liu Y, et al. Cediranib suppresses homology-directed DNA repair through down-regulation of BRCA1/2 and RAD51. Sci Transl Med. 2019;11:eaav4508.
  24. Kim JW, McKay RR, Radke MR, et al. Randomized Trial of Olaparib With or Without Cediranib for Metastatic Castration-Resistant Prostate Cancer: The Results From National Cancer Institute 9984. J Clin Oncol. 2023;41(4):871-880.
  25. Lloyd RL, Wijnhoven PWG, Ramos-Montoya A, et al. Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells. Oncogene. 2020;39(25):4869-4883.
  26. Reichert ZR, Devitt ME, Alumkal JJ, et al. Targeting resistant prostate cancer, with or without DNA repair defects, using the combination of ceralasertib (ATR inhibitor) and olaparib (the TRAP trial). J Clin Oncol. 2022;40(6):Supplement.

Emerging Therapeutic Options for Low-Grade Non-Invasive Bladder Cancer: Primary Chemoablation

Introduction


Bladder cancer remains the sixth most commonly diagnosed cancer in the United States, with an estimate of 82,290 incident cases in 2023.1 At diagnosis, approximately 75% of patients present with non-muscle invasive disease, with significant clinical heterogeneity observed within this disease group.2,3 Patients with initial low-grade Ta disease (i.e., confined to the mucosal lining) represent a unique patient cohort given their favorable long-term oncologic outcomes, given that they are more likely to recur than progress to life-threatening disease.4
Written by: Rashid K. Sayyid, MD, MSc University of Toronto Toronto, ON and Zachary Klaassen, MD, MSc Medical College of Georgia Augusta, Georgia, USA
References:
  1. American Cancer Society. Key Statistics for Bladder Cancer.
  2. Babjuk M, Burger M, Comperat EM, et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ)—2019 update. Eur Urol 2019; 76(5):639-57.
  3. Monteiro LL, Witjes JA, Agarwal PK, et al. ICUD-SIU International Consultation on Bladder Cancer 2017: management of non-muscle invasive bladder cancer. World J Urol 2019; 37(1):51-60.
  4. Hernandez V, Llorente C, de la Pena E, et al. Long-term oncological outcomes of an active surveillance program in recurrent low grade Ta bladder cancer. Urol Oncol 2016; 34(4):165.e19-23.
  5. Mossanen M, Gore JL. The Burden of Bladder Cancer Care – Direct and Indirect Costs. Curr Opin Urol 2014; 24(5):487-91.
  6. Zhou Z, Zhao S, Lu Y, et al. Meta-analysis of efficacy and safety of continuous saline bladder irrigation compared with intravesical chemotherapy after transurethral resection of bladder tumors. World J Urol, 2019; 37(6):1075.
  7. Sylvester RJ, et al. Systematic Review and Individual Patient Data Meta-analysis of Randomized Trials Comparing a Single Immediate Instillation of Chemotherapy After Transurethral Resection with Transurethral Resection Alone in Patients with Stage pTa-pT1 Urothelial Carcinoma of the Bladder: Which Patients Benefit from the Instillation? Eur Urol 2016; 69(2): 231-44.
  8. Perlis N, Zlotta AR, Beyene J, et al. Immediate post-transurethral resection of bladder tumor intravesical chemotherapy prevents non-muscle-invasive bladder cancer recurrences: an updated meta-analysis on 2548 patients and quality-of-evidence review. Eur Urol 2013; 64(3):421-30.
  9. Messing EM, Tangen CM, Lerner SP, et al. Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial. JAMA 2018; 319(18):1880-8.
  10. Arends TJH, Nativ O, Maffezzini M, et al. Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guérin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer. Eur Urol 2016; 69(6):1046-52.
  11. Arends TJH, van der Heijdem AG, Witjes JA. Combined chemohyperthermia: 10-year single center experience in 160 patients with nonmuscle invasive bladder cancer. J Urol 2014; 192(3):708-13.
  12. Shelley MD, Kynaston H, Court J, et al. A systematic review of intravesical bacillus Calmette-Guérin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int 2001; 88(3):209-16.
  13. Han RF, Pan JG. Can intravesical bacillus Calmette-Guérin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006; 67(6):1216-23.
  14. Shelley MD, Wilt TJ, Court J, et al. Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int 2004; 93(4):485-90.
  15. Bohle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 2003; 169(1):90-5.
  16. Popert RJ, Goodall J, Coptcoat MJ, et al. Superficial bladder cancer: the response of a marker tumour to a single intravesical instillation of epirubicin. Br J Urol 1994; 74(2):195-9.
  17. Mostafid AH, Porta N, Cresswell J, et al. CALIBER: a phase II randomized feasibility trial of chemoablation with mitomycin‐C vs surgical management in low‐risk non‐muscle‐invasive bladder cancer. BJU Int 2020; 125(6):817-26.
  18. Lindgren MS, Bue P, Azawi N, et al. The DaBlaCa-13 Study: Short-term, Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in Non-muscle-invasive Bladder Cancer-A Randomised Controlled Trial. Eur Urol 2020; 78(6):856-62.
  19. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial. Lancet Oncol 2020; 21(6):776-85.
  20. FDA approves mitomycin for low-grade upper tract urothelial cancer.
  21. Chevli KK, Shore ND, Trainer A, et al. Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial. J Urol 2022; 207(1):61-9.
  22. Prasad SM, Huang WC, Shore ND, et al. Treatment of Low-grade Intermediate-risk Nonmuscle-invasive Bladder Cancer With UGN-102 ± Transurethral Resection of Bladder Tumor Compared to Transurethral Resection of Bladder Tumor Monotherapy: A Randomized, Controlled, Phase 3 Trial (ATLAS). J Urol 2023; 101097JU0000000000003645.

PARP Inhibitor Monotherapy for Prostate Cancer Patients

Introduction

Over the past decade, there have been significant advances in defining the genomic landscape of prostate cancer. The landmark study by Pritchard et al. published in The New England Journal of Medicine in 2016 demonstrated that germline DNA-repair gene mutations were present in approximately 12% of metastatic prostate cancer patients, most commonly BRCA2 (5.3%), CHEK2 (1.9%), and ATM (1.6%). Significantly, the frequency of such mutations increases across the prostate cancer spectrum – 2% in patients with NCCN localized low-to-intermediate risk tumors, 6% in those with localized high-risk tumors, and as high as 24% in patients with metastatic castrate-resistant prostate cancer (mCRPC).1 This is of utmost clinical importance as such mutations, both inherited and acquired (i.e., somatic), represent actionable clinical targets for drug therapy.

Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are drugs that prevent the repair of DNA single-stranded breaks and promote their conversion to double-stranded breaks leading to a synthetic lethality. These agents are most effective in homologous recombination repair (HRR)-deficient tumors (e.g., BRCA1/2), due to their compromised ability to repair DNA double strand breaks.2 In addition to breast and ovarian malignancies, PARP inhibitors have gained regulatory approval for the treatment of mCRPC patients:

  • Rucaparib for BRCA1/2-mutated patients (FDA approved in 2020)3
  • Olaparib for HRR-mutated patients (FDA approved in 2020)4
  • Olaparib plus abiraterone for BRCA1/2-mutated patients (FDA approved in 2023)5
  • Niraparib plus abiraterone for BRCA1/2-mutated patients (FDA approved in 2023)6
  • Talazoparib plus enzalutamide for HRR-mutated patients (FDA approved in 2023)7

In this Center of Excellence article, we will provide an in-depth overview of the current evidence for PARP inhibitor monotherapy in prostate cancer, summarizing efficacy results from major trials and discussing the adverse event profile of these agents.

Current Evidence for PARP Inhibitor Monotherapy

Olaparib

TOPARP-A was a pivotal phase II trial of olaparib in mCRPC in which 50 patients were treated with olaparib 400 mg twice daily until disease progression.8 The primary endpoint was the composite response rate defined either as an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, or a ≥ 50% reduction in prostate-specific antigen (PSA50), or a reduction in the circulating tumor-cell count from ≥ 5 per 7.5 ml of blood to < 5 per 7.5 ml. All patients had prior treatment with docetaxel and 49 (98%) with abiraterone or enzalutamide. Sixteen of 49 (33%) evaluable patients had a response. Overall, 14 of the 16 responders had homozygous deletions, deleterious mutations, or both in DNA-repair genes — including BRCA1/2ATM, Fanconi’s anemia genes, and CHEK2.

This was followed by TOPARP-B, an open-label, phase II trial in which men with HRR-mutated mCRPC that had progressed on ≥1 taxane therapy were treated with olaparib 400 mg or 300 mg twice daily in a randomized fashion.9 The primary endpoint was identical to the TOPARP-A trial. A targetable HRR gene aberration was found in 161 of 592 (27.2%) patients who underwent a targeted next-generation tumor sequencing. However, sequencing could not be performed on 119 (17%) of consented patients because of insufficient or poor-quality tissue. The confirmed composite response rate was 54.3% in the 400 mg cohort and 39.1% in the 300 mg cohort (p=0.14). Median radiographic progression-free survival (rPFS) was 5.5 months (95% CI: 4.4 – 8.3) in the 400 mg cohort and 5.6 months (3.7 – 7.7) in the 300 mg cohort. The predefined criteria for success were met for the 400 mg regimen but not for the 300 mg regimen.

These promising results served as the ‘precursor’ for PROfound, a randomized, open-label, phase III trial of olaparib 300 mg twice daily versus physician’s choice of standard of care therapy in men with HRR-mutated mCRPC who had disease progression while receiving a novel hormonal agent (e.g., enzalutamide or abiraterone). Patients were assigned to one of two cohorts based on their HRR gene alteration. Cohort A included patients with BRCA1, BRCA2, or ATM alterations, irrespective of co-occurring alterations in any other HRR genes. Cohort B had patients with alterations in any of the other 12 HRR genes (BRIP1, BARD1, CDK12, CHEK 1/2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L). Patients within each cohort were randomized in 2:1 fashion to olaparib versus standard of care . The primary endpoint was the rPFS in cohort A.

Of the 4,425 enrolled patients, 4,047 had tumor tissue available for testing and only 2,792 (69%) were successfully sequenced. A qualifying alteration in one or more of the 15 HRR genes was detected in 778 of 2,792 patients (28%). Median rPFS was significantly longer in the olaparib group than in the standard of care group (7.4 months versus 3.6 months; HR: 0.34; 95% CI: 0.25 – 0.47; p<0.001).

figure-1-PARPi-monotherapy2x.jpg

The confirmed objective response rate (ORR) was 33% in the olaparib group and 2% in the standard of care  group (odds ratio 20.9; 95% CI: 4.2 – 379.2; p<0.001). The median time to pain progression was also significantly longer in the olaparib group (HR: 0.44; 95% CI: 0.22 – 0.91; p=0.02). The final overall survival (OS) analysis demonstrated that olaparib improved OS in cohort A from a median of 14.7 to 19.1 months (HR: 0.69, 95% CI: 0.50 – 0.97). Notably, 84% of patients with imaging-based disease progression had crossed over from the standard of care  arm to olaparib at the time of analysis, which highlights the efficacy of earlier use of olaparib in this setting.10

figure-2-PARPi-monotherapy2x.jpg

The data from PROfound formed the basis for the FDA-approval of olaparib 300 mg PO twice daily in men with HRR-mutated mCRPC after progression on enzalutamide or abiraterone.4

Rucaparib

The first PARP inhibitor to be approved by the FDA for the treatment of prostate cancer patients was rucaparib. On May 15, 2020, rucaparib was granted accelerated approval for patients with mCRPC and BRCA mutations (germline or somatic) who had progressed following treatment with androgen receptor-directed therapy and a taxane-based chemotherapy.3 This approval was based on the results of TRITON2, which was initially published in 202011 and most recently updated in 2023.12 TRITON2 is an international, open-label, phase II trial that evaluated the safety and efficacy of rucaparib 600 mg twice daily in mCRPC patients with DNA damage response (DDR) gene alterations who had progressed after 1–2 lines of an androgen receptor pathway inhibitor and one taxane-based chemotherapy. The efficacy cohort included 277 patients, of whom 172 (62.1%) had a deleterious germline or somatic BRCA alteration with 21.3%, 5.4%, 3.1%, 4%, and 4.7% having ATM, CDK12, CHEK2, PALB2, and other DDR gene mutations, respectively. A confirmed objective response was observed in 46% of BRCA patients with measurable disease (10% complete response). A superior response was observed among BRCA2 patients (48% versus 30% for BRCA1), which is potentially secondary to an increased frequency of biallelic mutations among BRCA2 patients and a greater coexistence of TP53 mutations among BRCA1-mutated men.13 The objective response was consistent irrespective of whether the BRCA mutation was somatic or germline and whether other DDR mutations were present or absent. All four patients with PALB2 mutations and measurable disease had an objective partial response, with none of the ATM-, CDK12-, CHEK2-mutated patients experiencing an objective response. A confirmed PSA50 response was observed in 53% and 55% of BRCA and PALB2-mutated patients, compared to 3.4–14% among patients with other DDR gene mutations. The median overall survival was 17.2 months for BRCA patients, compared to 11.1–14.6 months among ATM, CDK12, and CHEK2-mutated patients.

figure-3-PARPi-monotherapy2x.jpg

Following the promising results of TRITON2, the phase 3 TRITON3 trial was published in 2023. This was a randomized phase 3 trial of mCRPC patients with a BRCA1, BRCA2, or ATM alterations who experienced disease progression following treatment with a second-generation androgen receptor pathway inhibitor. Patients underwent 2:1 randomization to receive oral rucaparib (600 mg twice daily) or a physician’s choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median PFS according to independent review. There were 405 patients randomized to receive rucaparib (n=270) or the control group (n=135). At 62 months follow-up, imaging-based PFS was significantly prolonged in the rucaparib group compared to the control group, both in the BRCA subgroup (11.2 and 6.4 months, respectively; HR: 0.50; 95% CI: 0.36 – 0.69) and in the intention-to-treat population (10.2 and 6.4 months, respectively; HR: 0.61; 95% CI: 0.47 – 0.80; p<0.001 for both comparisons). No significant PFS benefit was observed in the ATM subgroup.

figure-4-PARPi-monotherapy2x.jpg

In the BRCA subgroup, the median OS was 24.4 versus 20.8 months in favor of rucaparib (HR: 0.81, 95% CI: 0.58 – 1.12, p=0.21).14

Talazoparib

TALAPRO-1 was an open-label, phase II trial that evaluated talazoparib 1 mg/day in patients with evidence of progressive mCRPC who had measurable soft-tissue disease and evidence of one of 11 DDR mutations who had progressed following taxane-based chemotherapy (48% both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide (98% of population). The primary endpoint was confirmed ORR. There were 128 patients enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumor activity population). After a median follow-up of 16.4 months, the ORR was 30% (95% CI: 21.2 – 39.6%).15

Niraparib

GALAHAD was a multicenter, open-label, single arm phase II trial of 289 mCRPC patients with DNA repair gene defects and disease progression following a prior next-generation androgen signaling inhibitor and a taxane, who received niraparib 300 mg orally once daily. The primary endpoint was ORR in patients with BRCA alterations and measurable disease. At a median follow-up of 10 months, the ORR in the measurable BRCA cohort was 34.2%. The median duration of objective response was 5.6 months. Conversely, the ORR in the measurable non-BRCA cohort was 10.6%. Median rPFS (8.1 versus 3.7 months) and OS (13.0 and 9.6 months) were both longer in the BRCA cohort, compared to the non-BRCA cohort.16

figure-5-PARPi-monotherapy2x.jpg

Management of Side Effects of PARP Inhibitors

The adverse event/safety profiles of all PARP inhibitors overlap considerably. The most common (any CTCAE grade) clinical side effects in phase III trials of rucaparib, olaparib and niraparib include:17

  • Nausea: ~75%
  • Fatigue: 60–70%
  • Vomiting: ~35%
  • Constipation: 20–40%
  • Dysgeusia: 10–40%
  • Anorexia: ~25%
  • Abdominal pain: 25–30%
  • Diarrhea: 20–30%
  • Headache: 20–25%
  • Cough: 10–15%

The most common (any CTCAE grade) lab abnormalities were:

  • Anemia: 40–50%
  • Thrombocytopenia: 15–60%
  • Neutropenia: 20–30%
  • Alanine aminotransferase (ALT) elevation: 5–36%
  • Aspartate aminotransferase (AST) elevation: 2–28%
  • Increased serum creatinine level: 10–15%

While nausea is the most common side effect of PARP inhibitor therapy, it tends to be mild in most cases. This side effect can be managed by taking the medication after a meal and an antiemetic (prochlorperazine or a 5-HT3 antagonist such as ondansetron) may be considered in patients who develop moderate or severe nausea and/or vomiting with PARP inhibitor therapy.

Close monitoring of patients following PARP inhibitor therapy initiation is required, particularly  in the first three months, as hematologic adverse effects usually occur early, but not invariably, and regular blood counts should continue while patients are on treatment. Anemia is the most common hematologic toxicity observed with PARP inhibitors, with grade 3–4 anemia observed in 22% of patients on olaparib, 27% of patients on rucaparib, and 31% of patients on niraparib first-line maintenance therapy ovarian cancer trials.18-21 The management of such events may include dose reductions and/or interruptions, with transfusions reserved for symptomatic anemic events or if the hemoglobin level falls to <7 g/dL. Thrombocytopenia appears to be more common with niraparib at 61%, as opposed to olaparib (14%) or rucaparib (28%). The niraparib FDA label thus recommends obtaining weekly platelet levels during the first month of therapy.

Elevated serum creatinine level occurs within the first few weeks of therapy and is thought to be an on-target effect due to the inhibition of renal transporter proteins. Thus, serum creatinine-based estimation of renal function may be inaccurate in patients receiving PARP inhibitor therapy. Alternative methods of glomerular filtration rate (GFR) estimation such as radionuclide scan or serum-cystatin C must be used in cases where a more accurate GFR estimate is necessary. Elevation of AST and ALT also tends to typically occur within the first two cycles and can be transient. Treatment interruption may not be required for mild AST/ALT elevations, but serum bilirubin levels must be checked in all patients to evaluate for drug-induced liver injury.

Owing to their mechanism of action, there was a concern regarding treatment-emergent myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with PARP inhibitor therapies. However, it appears that the risk of MDS/AML is <1.5%. Of the 2,351 patients treated in olaparib monotherapy trials, only 28 (<1.5%) developed MDS/AML. Of these, 25/28 patients had a BRCA mutation, two patients had a wild-type germline BRCA, and one patient had unknown BRCA mutation status. The duration of olaparib varied from < 6 months to > 2 years and all had received previous chemotherapy with platinum and/or other DNA damaging agents, or radiotherapy.17 If pancytopenia occurs at any point during PARP inhibitor therapy, treatment must be interrupted as per guidelines for the drug, and appropriate evaluation for MDS and AML must be undertaken. Therapy must be discontinued permanently if a diagnosis of MDS or AML is confirmed.

Another important consideration is the potential for clinically-significant drug-drug interactions (DDI) with all PARP inhibitors. Rucaparib and olaparib are primarily metabolized by different members of the cytochrome P450 enzyme family, resulting in only a partial overlap in DDIs. Niraparib is metabolized in the liver by carboxylesterase-catalyzed amide hydrolysis with cytochrome P450 playing only a negligible role.22 Many commonly used drugs (such as phenytoin, carbamazepine, ketoconazole, ciprofloxacin, digoxin) have uni- or bi-directional interactions with PARP inhibitors. Thus, careful attention must be paid to minimize DDI by avoiding, discontinuing, adjusting the dose, or clinical/lab monitoring of these medications before and during PARP therapy. Involving a dedicated oncology pharmacist, where available, may be a valuable aid in this treatment setting.

Conclusions and Future Directions

PARP inhibitor monotherapy has demonstrated promising outcomes for the treatment of HRR-mutated mCRPC patients with evidence of disease progression following treatment with an androgen receptor pathway inhibitor and/or taxane-based chemotherapy. As a result, there has been an increased interest in ‘moving up’ these agents along the disease spectrum, as well as combining PARP inhibitors with other agents that may have a synergistic mechanism of action.

Published March 2024

Written by: Rashid K. Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, ON and Zachary Klaassen, MD, MSc Associate Professor Wellstar MCG Health Augusta, GA
References:
  1. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016;375:443-453.
  2. Xie T, Dickson K, Yee C, et al. Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival. Cancers (Basel). 2022;14(19):4621.
  3. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate. Accessed on March 8, 2024.
  4. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer. Accessed on March 8, 2024.
  5. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration. Accessed on March 8, 2024.
  6. FDA approves niraparib and abiraterone acetate plus prednisone for BRCA-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-niraparib-and-abiraterone-acetate-plus-prednisone-brca-mutated-metastatic-castration. Accessed on March 8, 2024.
  7. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate. Accessed on March 8, 2024.
  8. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697-1708.
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  10. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;383:2345-2357.
  11. Abida W, Campbell D, Patnaik A, et al. Non-BRCA DNA Damage Repair Gene Alterations and Response to the PARP Inhibitor Rucaparib in Metastatic Castration-Resistant Prostate Cancer: Analysis From the Phase II TRITON2 Study. Clin Cancer Res. 2020;26(11):2487-2496.
  12. Abida W, Campbell D, Patnaik A, et al. Rucaparib for the Treatment of Metastatic Castration-resistant Prostate Cancer Associated with a DNA Damage Repair Gene Alteration: Final Results from the Phase 2 TRITON2 Study. Eur Urol 2023;84:321-330.
  13. Taza F, Holler AE, Fu W, et al. Differential Activity of PARP Inhibitors in BRCA1- Versus BRCA2-Altered Metastatic Castration-Resistant Prostate Cancer. JCO Precis Oncol 2021;5:PO.21.00070.
  14. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N Engl J Med. 2023;388:719-732.
  15. de Bono JS, Mehra N, Scagliotti GV, et al. Talazoparib monotherapy in metastatic castration-resistant prostate cancer with DNA repair alterations (TALAPRO-1): an open-label, phase 2 trial. Lancet Oncol. 2021;22(9):1250-1264.
  16. Smith MR, Scher HI, Sandhu S, et al. Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2022;23(3):362-373.
  17. LaFargue C, Dal Molin DZ, Sood AK, et al. Exploring and comparing adverse events between PARP inhibitors. Lancet Oncol. 2019;20(1):e15-e28.
  18. Gonzalez-Martin A, Pothuri B, Vergote I, et al: Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381:2391-2402.
  19. Moore K, Colombo N, Scambia G, et al: Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379:2495-2505.
  20. Banerjee S, Moore KN, Colombo N, et al: Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-Year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22:1721-1731.
  21. Monk BJ, Parkinson C, Lim MC, et al: A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA-MONO/GOG-3020/ENGOT-ov45). J Clin Oncol. 2022;40:3952-3964.
  22. Sandhu SK, Schelman WR, Wilding G, et al. The poly (ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;13(9):882-892.

The Treatment Landscape of Metastatic Urothelial Carcinoma: Second-Line Systemic Therapy

Introduction


For patients with metastatic urothelial carcinoma, first line therapy for cisplatin eligible patients remains platinum-based chemotherapy1 (followed by maintenance avelumab2), whereas those that are cisplatin ineligible may receive gemcitabine + carboplatin3 (followed by maintenance avelumab2), pembrolizumab,4 or pembrolizumab + enfortumab vedotin.5 Unfortunately, ~50% of patients will eventually have disease progression following first line therapy, which has historically been associated with a dismal prognosis.
Written by: Zachary Klaassen, MD, MSc Associate Professor of Urology Urologic Oncologist Medical College of Georgia, Georgia Cancer Center Augusta, GA and Rashid Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, Ontario, Canada
References:
  1. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18: 3068-3077.
  2. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383: 1218-1230.
  3. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30: 191-199.
  4. Powles T, Csoszi T, Ozguroglu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22: 931-945.
  5. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023;41: 22-31.
  6. Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002;20: 937-940.
  7. Galsky MD, Mironov S, Iasonos A, Scattergood J, Boyle MG, Bajorin DF. Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma. Invest New Drugs. 2007;25: 265-270.
  8. McCaffrey JA, Hilton S, Mazumdar M, et al. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997;15: 1853-1857.
  9. Bellmunt J, Theodore C, Demkov T, et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol. 2009;27: 4454-4461.
  10. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376: 1015-1026.
  11. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017;18: 312-322.
  12. Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol. 2017;35: 2117-2124.
  13. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019;381: 338-348.
  14. Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15: 25-41.
  15. Sideris S, Aoun F, Zanaty M, et al. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder cancer. Mol Clin Oncol. 2016;4: 1063-1067.
  16. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19: 2638-2646.
  17. Yu EY, Petrylak DP, O'Donnell PH, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021;22: 872-882.

The Quickly Evolving Treatment Landscape of Metastatic Urothelial Carcinoma: A New Standard of Care in First-Line Systemic Therapy

Introduction

Metastatic urothelial carcinoma is associated with a poor prognosis, with an estimated 17,000 deaths annually in the United States from this disease.1 Platinum-based chemotherapy had long been considered the standard of care first line treatment for platinum-eligible patients with metastatic urothelial carcinoma.
Written by: Zachary Klaassen, MD, MSc Associate Professor of Urology Urologic Oncologist Medical College of Georgia, Georgia Cancer Center Augusta, GA and Rashid Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, Ontario, Canada
References:
  1. American Cancer Society. Key Statistics for Bladder Cancer. Accessed on February 26, 2024.
  2. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18: 3068-3077.
  3. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19: 2638-2646.
  4. Powles T, Csoszi T, Ozguroglu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(7): 931-945.
  5. Galsky MD, Arija JAA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236): 1547-1557.
  6. Powles TB, Perez Calderrama B, Gupta S, et al. LBA6 EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). Annal Oncol. 2023;34(Suppl 2): S1340.
  7. van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023;389(19): 1778-1779.
  8. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer.  Accessed on February 26, 2024.
  9. U.S. Food and Drug Administration Accepts for Priority Review Bristol Myers Squibb’s Application for Opdivo (nivolumab) in Combination with Cisplatin-Based Chemotherapy for the First-Line Treatment of Adult Patients with Unresectable or Metastatic Urothelial Carcinoma. Accessed on February 26, 2024.U.S. Food and Drug Administration Accepts for Priority Review Bristol Myers Squibb’s Application for Opdivo (nivolumab) in Combination with Cisplatin-Based Chemotherapy for the First-Line Treatment of Adult Patients with Unresectable or Metastatic Urothelial Carcinoma. Accessed on February 26, 2024.
  10. Klumper N, Ralser DJ, Ellinger J, et al. Membranous NECTIN-4 Expression Frequently Decreases during Metastatic Spread of Urothelial Carcinoma and Is Associated with Enfortumab Vedotin Resistance. Clin Cancer Res. 2023;29(8): 1496-1505.
  11. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021;384: 1125-35.
  12. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med. 2017;376(11): 1015-1026.
  13. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29: 2432-2438.
  14. Sternberg CN, Yagoda A, Scher HI, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol. 1985;133: 403-407.
  15. Sternberg CN, Yagoda A, Scher HI, et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer. 1989;64: 2448-2458.
  16. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999;17: 3173-3181.
  17. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42: 50-54.
  18. Lee YS, Ha MS, Tae JH, et al. Gemcitabine-cisplatin versus MVAC chemotherapy for urothelial carcinoma: a nationwide cohort study. Sci Rep. 2023;13: 3682.
  19. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383: 1218-1230.
  20. Powles T, Park SH, Caserta C, et al. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After ≥2 Years of Follow-Up. J Clin Oncol. 2023;41: 3486-3492.
  21. Powles T, Sridhar SS, Loriot Y, et al. Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial. Nat Med. 2021;27: 2200-2211

BCG-unresponsive Non-Muscle Invasive Bladder Cancer: Immune Checkpoint Inhibitors

Introduction


Intravesical Bacillus Calmette-Guerin (BCG) currently remains the standard-of-care, guideline recommended treatment of choice in the adjuvant setting for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) due to its ability to reduce the risk of disease recurrence and, more importantly, disease progression.1-3 However, despite adequate BCG treatment, defined as receipt of at least five doses of the initial six-dose induction course and at least 2/3 maintenance doses or at least 2/6 doses of the second induction course, up to 50% of such patients will develop a BCG-refractory, relapsing, or failure state.4 Currently, radical cystectomy remains the gold standard approach in this setting.1 However, many patients are either unfit or refuse cystectomy. As such, bladder-sparing approaches in this setting are of utmost importance.
Written by: Rashid K. Sayyid, MD, MSc University of Toronto Toronto, ON and Zachary Klaassen, MD, MSc Medical College of Georgia Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer.
  2. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  3. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Review. 2020;1(1):CD011935.
  4. Babjuk M, Burger M, Comperat EM, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 Update. Eur Urol. 2019;76(5):639–57.
  5. Steinberg R, Bahnson R, Brosman S, et al. Efficacy and Safety of Valrubicin for the Treatment of Bacillus Calmette-Guerin Refractory Carcinoma in Situ of the Bladder. J Urol. 200;163(3):761-7.
  6. Bacillus Calmette-Guérin-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. 2018.
  7. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer.
  8. FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.
  9. Kates M, Matoso A, Choi W, et al. Adaptive Immune Resistance to Intravesical BCG in Non–Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials. Clin Cancer Res. 2020;26(4):882-91.
  10. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-30.
  11. Necchi A, Roumiguié M, Esen AA, et al. Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial. J Clin Oncol. 2023;41(Supp 6):LBA442.
  12. Alanee S, Sana S, El-Zawahry A, et al. Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous Bacillus Calmette-Guérin treatment. World J Urol. 2021;39(10):3807-13.
  13. Meghani K, Cooley LF, Choy B, et al. First-in-human Intravesical Delivery of Pembrolizumab Identifies Immune Activation in Bladder Cancer Unresponsive to Bacillus Calmette-Guérin. Eur Urol. 2022;82(6):602-10.
  14. Li R, Sexton WJ, Dhillon J, et al. A Phase 2 Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder. Clin Cancer Res. 2023.
  15. Kowalski M, Guindon J, Brazas L, et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin. J Urol. 2012;188(5):1712-8.
  16. Gurram S, Bellfield S, Dolan R, et al. PD09-04 Interim analysis of a phase I single-arm study of the combination of durvalumab (Medi4736) and vicinium (Oportuzumab Monatox, Vb4-845) in subjects with high-grade non-muscle-invasive bladder cancer previously treated with Bacillus Calmette-Guerin (Bcg). J Urol. 2021;206(Suppl 3):e120.
  17. Black PC, Tangen C, Singh P, et al. Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816). J Clin Oncol;2020(Suppl):5022.
  18. Shore ND, Powles T, Bedke J, et al. A phase 3 study of the subcutaneous programmed cell death protein 1 inhibitor sasanlimab as single agent for patients with bacillus Calmette-Guérin, unresponsive high-risk, non-muscle invasive bladder cancer: CREST Study Cohort B. J Clin Oncol. 2022;40(Suppl 16):40.
  19. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med. 2021;384:2102-14.
  20. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007;109(8):1499-505.
  21. Hudolin T, Mengus C, Coulot J, et al. Expression of Indoleamine 2,3-Dioxygenase Gene is a feature of poorly differentiated non-muscle-invasive urothelial cell bladder carcinomas. Anticancer Res. 2017;37(3):1375-80.
  22. Tabernero, et al. BMS-986205, an indoleamine 2,3-dioxygenase 1 inhibitor (IDO1i), in combination with nivolumab (NIVO): Updated safety across all tumor cohorts and efficacy in pts with advanced bladder cancer (advBC). J Clin Oncol. 2018;36(Suppl 15):4512.

Lessons Learned from COVID-19 in the Care of NMIBC Patients: Insights from the CISTO Investigators

Ongoing analyses of disruptions to care during the COVID-19 Public Health Emergency (PHE) continue to help identify important insights on how the healthcare system adapted to the pandemic, as well as how cancer patients may have been affected by the PHE. The PHE led to significant disruptions in clinical cancer care, including the closure of operating rooms for elective surgeries and the repurposing of clinical visits to telemedicine, to accommodate COVID-19 patients and conserve resources like personal protective equipment. In their recent publication, Gore et al. present their data from a monthly survey initiated in May 2020 among urologists in a large pragmatic trial for high-risk bladder cancer to assess the impact of these disruptions on the surgical and clinical management of bladder cancer.

BCG-Unresponsive Non-Muscle Invasive Bladder Cancer: Review of Intravesical Chemotherapy and Photodynamic Therapy

Introduction

Intravesical Bacillus Calmette-Guerin (BCG) remains the current standard-of-care, guideline-recommended treatment of choice in the adjuvant setting for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) due to its ability to reduce the risk of disease recurrence and, more importantly, disease progression.1-3 Despite adequate BCG treatment up to 50% of patients will develop a BCG-refractory, relapsing, or failure state.4

Over the last several years, there has been a plethora of data in the BCG unresponsive disease space, leading to FDA approvals for pembrolizumab in January 2020 and nadofaragene firadenovec in December 2022.6 Many of these novel immune-based treatments overcome some of the limitations of older agents in this setting,7 particularly those related to short durations of exposure limiting their efficacy.8 This same concept of extending the intravesical exposure time has recently been extrapolated to the intravesical chemotherapeutic treatment landscape, where we have witnessed the emergence of novel agents with prolonged mechanisms of action and alternate methods of administration. In this Center of Excellence article, we will discuss the currently available evidence and ongoing studies for intravesical chemotherapeutic agents and photodynamic therapy in the BCG unresponsive NMIBC disease space.


Gemcitabine + Docetaxel

In 2020, the results of a multicenter, retrospective analysis evaluating sequential gemcitabine plus docetaxel in patients with recurrent NMIBC and a history of intravesical BCG treatment were reported. In this study, all patients received intravesical gemcitabine (1 gm/50 ml sterile water or saline) for 60 to 90 minutes, after which it was drained and intravesical docetaxel (37/5 mg/50 ml saline) was instilled and held for 1-2 hours. To minimize side effects secondary to the irritative effects of gemcitabine (pH 2.5), 1,300 mg of oral sodium bicarbonate was given the evening before and the morning of each instillation to alkalinize the urine. The induction regimen was given once weekly for 6 weeks, followed by monthly maintenance for up to 24 months in the majority of the participating institutions. Surveillance was performed in accordance with institutional/national guidelines.

This analysis included 276 patients with a median age of 73 years. The median number of prior BCG courses was 2 (range: 1 to 8), with 38% of patients meeting the BCG unresponsive disease definition. From an efficacy standpoint, the 1- and 2-year recurrence-free survival rates were 60% and 46%, respectively, with similar recurrence rates observed for patients with CIS versus papillary-only disease. The high-grade recurrence-free survival rates in the overall cohort at 1 and 2 years were 65% and 52%, respectively:

figure-1-intravesical-chemo.jpg

Among patients with BCG unresponsive disease, the 2-year high-grade recurrence-free survival rates were 50% and 58% for CIS and papillary disease-alone cases, respectively:

figure-2-intravesical-chemo.jpg

Overall, 43/276 patients (15.6%) underwent a radical cystectomy, at a median follow-up of 11.3 months, and 11 patients (4%) had evidence of progression to muscle invasive disease. The most common side effects were frequency/urgency and dysuria, with 41% of patients reporting symptoms during treatment, but only 9.3% having symptoms that impacted the treatment schedule. There were no reported treatment-related deaths.9

Long-term follow-up of a subset of this cohort from the University of Iowa was recently published in 2023. This analysis included 97 patients (35% BCG unresponsive), with a median follow-up of 49 months. The 3-month complete response rate was 74%, with a median duration of response of 25 months. The high-grade recurrence-free survival rates were:

  • 1 year: 60%
  • 2 years: 50%
  • 5 years: 30%
There were no significant differences in these rates between the overall and BCG unresponsive patients. During follow-up, 20 patients (20.6%) underwent a cystectomy and 15 patients (15.5%) experienced disease progression. The 5-year progression-free, cystectomy-free, cancer-specific, and overall survival rates were 82%, 75%, 91%, and 64%, respectively.10


Device-assisted Administration of Intravesical Chemotherapy

TAR-200

TAR-200/gemcitabine (JNJ-17000139) is a novel drug delivery system that allows for the sustained local release of gemcitabine intravesically, relying on an osmotic system as illustrated below:

figure-3-intravesical-chemo.jpg

Evaluation of urine and plasma gemcitabine concentrations over a 7-day period demonstrates the ability of TAR-200 to provide sustained, local delivery of gemcitabine while limiting systemic toxicity. As demonstrated in the figure below, intravesical instillation of gemcitabine (green curve) is associated with a sharp increase/decrease in the gemcitabine urine concentration, which is non-sustained beyond day 1. Conversely, we see an increase in the urinary gemcitabine concentration between days 1 and 3 with TAR-200 (blue curve), followed by a gradual decline with measurable levels detected until at least day 7. Importantly, no gemcitabine is detected in the plasma of patients receiving TAR-200.

figure-4-intravesical-chemo.jpg

SunRISe-1 is a randomized trial of BCG-unresponsive, high-risk NMIBC patients with CIS +/- papillary disease, who did not receive a radical cystectomy. Patients underwent stratified randomization (by presence or absence of concomitant papillary disease) in a 2:1:1 fashion to either:

  • Cohort 1: TAR-200 + cetrelimab (PD-1 inhibitor)
  • Cohort 2: TAR-200 alone (target sample size 50, currently enrolled: 23)
  • Cohort 3: Cetrelimab alone (target sample size 50, currently enrolled: 24)
Patients received TAR-200 every 3 weeks for the first 24 weeks, followed by every 12 weeks through week 96. Patients in the cetrelimab group received the drug through week 78. The primary endpoint was overall complete response. At AUA 2023, Dr. Sia Daneshmand presented the first results from the monotherapy arms of TAR-200 and cetrelimab alone groups of SunRISe-1 from a planned futility analysis (n=47 patients).

The median patient age was 70 – 72 years, pure CIS was present in 70% and 65% of patients in the TAR-200 and cetrelimab groups, respectively, and the median total doses of prior BCG were 12 in each arm. From an efficacy standpoint, 73% of patients in the TAR-200 arm achieved a complete response (median duration of response not yet reached), defined based on the results of cystoscopy, centrally assessed urine cytology, and mandated biopsy at weeks 24 and 48. The CR rate in the cetrelimab arm was 38%.

figure-5-intravesical-chemo.jpg

Overall, most adverse events in the TAR-200 group were grade ≤2, with those reported in the cetrelimab group similar to that expected and observed with other PD-1 agents. 9% and 4% of patients discontinued TAR-200 and cetrelimab due to treatment-related adverse events. In each arm, 1 patient had treatment-related serious adverse events and 2 patients had treatment-related grade ≥3 adverse events. No deaths were observed in the study.11

figure-6-intravesical-chemo.jpg

Given these promising findings from the TAR-200 monotherapy arm, Janssen announced that they will be suspending further enrollment to the TAR-200 + cetrelimab arm.


Radiofrequency-induced Thermochemotherapy

In 2009, the results of a multi-institutional analysis of 51 patients from 15 European centers receiving mitomycin combined with intravesical hyperthermia in patients with mainly BCG-failing CIS (35/51) were published. Patients received mitomycin via the Synergo® system SB-TS 101, which uses an intravesical microwave applicator to deliver hyperthermia to the bladder wall via direct irradiation, weekly for 6–8 weeks, followed by 4–6 sessions every 6–8 weeks. Of 49 evaluable patients, there was evidence of a complete CIS response (negative biopsy and cytology) at 3 months in 45 patients (92%). Patients had similar outcomes irrespective of whether they met the BCG failure definition or not. Among the 45 responders, 49% had a recurrence at a median follow-up of 22 months. The most common adverse events were bladder spasms (13.1%), pain (12.7%), and dysuria (6.2%), and were generally mild in severity.12

A follow-up analysis of 150 patients who received ≥6 radiofrequency mitomycin instillations (induction and maintenance) was reported in 2018. All included patients had either pathology or cystoscopy plus cytology available at 6 months of follow-up. Of these 150 patients, 50 (33.3%) had BCG-unresponsive disease, with a 6-months complete response rate of 36% in this subgroup. The two-year recurrence-free survival rate was 82.6%, with a three-year cystectomy-free rate of 71.4%. Treatment discontinuation due to adverse events occurred in 13.4% of patients receiving induction treatment and 17.8% of those receiving maintenance instillations.13


Hyperthermic Intravesical Chemotherapy

In 2018, de Joeng et al. reported the results of hyperthermic intravesical chemotherapy (HIVEC) in 52 patients with BCG unresponsive NMIBC. Patients received intravesical instillations of mitomycin (80 mg in 50 mL of distilled water) that were extravesically heated up to 41-43°C and recirculated during 60 minutes at 200 m/min at stable pressure. All instillations were conducted with the Combat BRS system V2.0. The 3-months complete response rate was 75%. By 12 months follow-up, 47% of patients had remained disease-free. The overall median disease-free survival was 17.7 months and was significantly longer in those with papillary disease at 28.8 months versus 17.7 months in those with CIS. Patients in the ‘very high risk’ BCG unresponsive group had the shortest disease-free survival duration at 12.1 months. Any adverse event was reported in 69% of patients, with almost all grade 1-2 in severity, most common of which was urinary frequency/urgency (35%), urinary tract pain (15%), and bladder spasms (7%).14

figure-7-intravesical-chemo.jpg

In 2022, results of the multi-institutional Hyperthermic Chemotherapy registry (HIVEC-E) were published. These included a total of 1,028 patients, with 172 (21%) and 74 (9%) having disease classified as BCG unresponsive and failure, respectively. The 12- and 24-months recurrence-free survival rates for the BCG unresponsive cohort were 78.1% and 57.4%, respectively. Among patients in the BCG unresponsive cohort, the 24-months recurrence-free survival rates were superior for those papillary only disease (64.5% versus 43.6% for those with CIS). Minor and severe adverse events occurred in 26% and 2% of patients, respectively.15


Photodynamic Therapy

TLD-1433 is a novel ruthenium-based photosensitizer that selectively binds to bladder cancer cells. When activated by a 520 nm intravesical laser (TLC-3200) under general anesthesia (90 J/cm2 of laser light), it generates cytotoxic singlet oxygen and radical oxygen species, leading to cell death. PDT is also known to induce an antitumor cascade of immune signaling.16,17

figure-8-intravesical-chemo.jpg

At ASCO GU 2023, Dr. Girish Kulkarni presented the interim results of a phase II trial evaluating this intravesical photo dynamic therapy in patients with BCG unresponsive CIS. At the time of presentation, the trial had enrolled 52 patients (70% pure CIS, 20% CIS + HG T1, 10% CIS + Ta). This was a heavily pre-treated cohort, with 21% having >19 prior BCG instillations. A complete response, defined by a negative cystoscopy and cytology, was observed in 54% of patients. Among the 12 patients who had available follow-up at 450 days, 8 (67%) had a complete response. While 9/52 patients experienced a serious adverse event, none were deemed directly treatment-related per the Data Safety Monitoring Board.18


Enfortumab Vedotin

Enfortumab vedotin (EV) is a Nectin-4 targeted antibody-drug conjugate. Nectin-4 is highly expressed on bladder tumor cells, making it an attractive target for such agents. Systemic use of EV has previously demonstrated an overall survival benefit in the 3rd line setting for patients with locally advanced or metastatic urothelial carcinoma, who had previously received platinum-based therapy and a PD-1 or PD-L1 inhibitor (EV-301).19 Based on its demonstrated benefit in locally advanced/metastatic urothelial carcinoma, EV is currently being evaluated in earlier settings. EV-104 (NCT05014139) is a phase 1, open-label, multicenter, dose-escalation, and dose-expansion study of intravesical EV in adults with high-risk BCG-unresponsive NMIBC (CIS +/- papillary disease) who are ineligible for or refuse radical cystectomy. The primary study objectives are to evaluate the safety and tolerability of intravesical EV and determine the maximum-tolerated and recommended phase II doses of intravesical EV.

Similar in concept to BCG and intravesical chemotherapy regimens, the EV-104 treatment regimen will include an induction phase, whereby patients will receive intravesical EV weekly for 6 weeks followed by monthly maintenance for a total of 9 additional EV doses. Patients will undergo cystoscopy and cytology every 3 months and annual upper tract imaging.

figure-9-intravesical-chemo.jpg

The study is currently enrolling in the United States (since January 2022) with additional sites planned in Canada and Europe, including the UK.

Erdafitinib

Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor that is approved for locally advanced or metastatic urothelial carcinoma in adults with FGFR3/2 alterations who have progressed during or after at least one line of platinum-containing chemotherapy.20 THOR-2 is a multi-cohort, phase II trial of erdafitinib in patients with high-risk NMIBC, with Cohort 2 including patients with BCG-unresponsive CIS (+/- papillary disease) and FGFR3/2 alterations. In this cohort, patients received continuous oral erdafitinib 6 mg once daily.

Interim results were presented at ASCO GU 2023 by Dr. James Catto. At time of presentation, Cohort 2 had enrolled 10 patients with a median age of 72 years. The complete response rates at the 1st (Cycle 3, Day 1) and 2nd evaluations (Cycle 6, Day 1) were 100% and 75%, respectively. At a median follow-up of 10 months, the median duration of response was 3.0 months. Grade 3 or worse treatment-related adverse events occurred in 3 patients (30%), and included dry mouth, stomatitis, nail disorder, onychomadesis, acute kidney injury, chronic kidney disease, sepsis, and hypotension. One patient discontinued treatment due to adverse events. There were no treatment-related deaths.


Conclusions

Intravesical chemotherapeutic agents have emerged as promising treatment options for patients with BCG unresponsive NMIBC. Given its ease of administration and wide availability, the intravesical combination of gemcitabine plus docetaxel has emerged as one of the most commonly used treatments in this setting in clinical practice. TAR-200, via a local sustained release of gemcitabine, demonstrates excellent early response rates in SunRISE-1. These agents add to the growing armamentarium in the BCG unresponsive disease space with future regulatory approvals by the FDA contingent on further follow-up of current and future studies of these agents.

table-1-intravesical-chemo.jpg

Published September 2023
Written by: Rashid K. Sayyid, MD, MSc University of Toronto Toronto, ON and Zachary Klaassen, MD, MSc Medical College of Georgia Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer. https://uroweb.org/guidelines/non-muscle-invasive-bladder-cancer. Accessed on July 30, 2023.
  2. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  3. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Review. 2020;1(1):CD011935.
  4. Babjuk M, Burger M, Comperat EM, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 Update. Eur Urol. 2019;76(5):639–57.
  5. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer. Accessed on July 30, 2023.
  6. FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-adstiladrin-nadofaragene-firadenovec-vncg-patients-high-risk#:~:text=On%20December%2016%2C%202022%2C%20the,with%20or%20without%20papillary%20tumors. Access on July 30, 2023.
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  10. Chevuru PT, McElree IM, Mott SL, et al. Long-term follow-up of sequential intravesical gemcitabine and docetaxel salvage therapy for non-muscle invasive bladder cancer. Urol Oncol. 2023;41(3):148.e1-7.
  11. Daneshmand S, van der Heijden MS, Jacob JM, et al. LBA02-03 FIRST RESULTS FROM SunRISE-1 IN PATIENTS WITH BCG UNRESPONSIVE HIGH-RISK NON–MUSCLE-INVASIVE BLADDER CANCER RECEIVING TAR-200 IN COMBINATION WITH CETRELIMAB, TAR-200, OR CETRELIMAB ALONE. J Urol. 2023;209(Suppl 4):e1187.
  12. Witjes JA, Hendricksen K, Gofrit O, Risi O, Nativ O. Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo® working party. World J Urol. 2009;27:319-24.
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  16. Alzeibak R, Mishchenko TA, Shilyagina NY, et al. Targeting immunogenic cancer cell death by photodynamic therapy: past, present and future. J Immunother Cancer. 2021;9:e001926.
  17. Meng Z, Zhou X, Xu J, et al. Light-triggered in situ gelation to enable robust photodynamic-immunotherapy by repeated stimulations. Adv Mater. 2019;31:e1900927.
  18. Kulkarni GS, Richards KA, Black PC, et al. A phase II clinical study of intravesical photo dynamic therapy in patients with BCG-unresponsive NMIBC (interim analysis). J Clin Oncol. 2023;6(Suppl):528.
  19. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021;384:1125-35.
  20. Loriot Y, Necchi A, Park SH, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2019;381:338-48.

CMS Releases Final Rule to Broaden Access to Health Data and Improve Prior Authorization

In January 2024, the Centers for Medicare & Medicaid Services (CMS) finalized the CMS Interoperability and Prior Authorization Final Rule (CMS-0057-F). This regulation mandates that Medicare Advantage (MA) organizations, Medicaid and the Children’s Health Insurance Program (CHIP) fee-for-service (FFS) programs, Medicaid managed care plans, CHIP managed care entities, and Qualified Health Plan (QHP) issuers on the Federally-Facilitated Exchanges (FFEs), collectively referred to as "impacted payers," enhance the digital exchange of healthcare information and streamline the prior authorization process for healthcare services and products. These measures aim to simplify prior authorization, alleviate burdens on patients, healthcare providers, and payers, and are projected to yield estimated savings of about $15 billion over a decade.

The Current Treatment Landscape of BCG-unresponsive Non-Muscle Invasive Bladder Cancer: N-803 and Viral/Bacterial-Based Therapies

Introduction


Intravesical Bacillus Calmette-Guerin (BCG) currently remains the standard-of-care, guideline recommended treatment of choice in the adjuvant setting for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) due to its ability to reduce the risk of disease recurrence and disease progression.1-3 However, despite adequate BCG, up to 50% of patients develop a BCG-refractory, relapsing, or failure state.4 Currently, radical cystectomy remains the gold standard approach in this setting.1 However, many patients are either unfit or refuse cystectomy.
Written by: Rashid K. Sayyid, MD, MSc, University of Toronto, Toronto, ON and Zachary Klaassen, MD, MSc, Medical College of Georgia, Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer.
  2. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  3. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Review. 2020;1(1):CD011935.
  4. Babjuk M, Burger M, Comperat EM, et al. European Association of Urology Guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) - 2019 Update. Eur Urol. 2019;76(5):639–57.
  5. Steinberg R, Bahnson R, Brosman S, et al. Efficacy and Safety of Valrubicin for the Treatment of Bacillus Calmette-Guerin Refractory Carcinoma in Situ of the Bladder. J Urol. 200;163(3):761-7.
  6. Bacillus Calmette-Guérin-unresponsive nonmuscle invasive bladder cancer: developing drugs and biologics for treatment guidance for industry. 2018.
  7. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer.
  8. FDA D.I.S.C.O. Burst Edition: FDA approval of Adstiladrin (nadofaragene firadenovec-vncg) for patients with high-risk Bacillus Calmette-Gu√©rin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors. 
  9. Kates M, Matoso A, Choi W, et al. Adaptive Immune Resistance to Intravesical BCG in Non–Muscle Invasive Bladder Cancer: Implications for Prospective BCG-Unresponsive Trials. Clin Cancer Res. 2020;26(4):882-91.
  10. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-30.
  11. Necchi A, Roumiguié M, Esen AA, et al. Pembrolizumab (pembro) monotherapy for patients (pts) with high-risk non–muscle-invasive bladder cancer (HR NMIBC) unresponsive to bacillus Calmette–Guérin (BCG): Results from cohort B of the phase 2 KEYNOTE-057 trial. J Clin Oncol. 2023;41(Supp 6):LBA442.
  12. Li R, Sexton WJ, Dhillon J, et al. A Phase 2 Study of Durvalumab for Bacillus Calmette-Guerin (BCG) Unresponsive Urothelial Carcinoma In Situ of the Bladder. Clin Cancer Res. 2023.
  13. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 Superagonist NAI in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer. N Engl J Med Evid. 2023;2(1).
  14. O’Donnell MA, Lilli K, Leopold C, National Bacillus Calmette-Guerin/interferon phase 2 investigator G Interim results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alfa-2b for superficial bladder cancer. J Urol. 2004;172(3):888–93.
  15. Boorjian SA, Alemozaffar M, Konety BR, Shore ND, Gomella LG, Kamat AM, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 2021;22(1):107–117.
  16. Friedlander TW, Weinberg VK, Yeung A, et al. Activity of intravesical CG0070 in Rb-inactive superficial bladder cancer after BCG failure: Updated results of a phase I/II trial. J Clin Oncol. 2012 (Supplement).
  17. Packiam VT, Lamm DL, Barocas DA, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urol Oncol. 2018;36(10):440-7.
  18. Li R, Steinberg GD, Uchio EM, et al. CORE1: Phase 2, single-arm study of CG0070 combined with pembrolizumab in patients with nonmuscle-invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guerin (BCG). J Clin Oncol. 2022;40(Suppl):4597.
  19. Bandari JJZ, Belani K, Brown E, Metcalf M, Nanayakkara N. Phase 1a/b safety study of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer (ADVANCED-1). J Clin Oncol. 2022;40(6):TPS4620.
  20. Sun W, Bandari J, Zummo J, et al. Phase 1b/2 dose expansion, open-label study to evaluate safety and anti-tumor activity of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer. J Clin Oncol. 2023;41(Suppl):TPS4618.
  21. Kowalski M, Guindon J, Brazas L, et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guérin. J Urol. 2012;188(5):1712-8.
  22. Shore N, O’Donnell M, Keane T, et al. PD03-02: Phase 3 Results of Vicinium in BCG-Unresponsive Non-Muscle Invasive Bladder Cancer. J Urol. 2020;Supp 4:e72.

Cretostimogene Grenadenorepvec: At the CORE and Forming BONDs in High-Risk NMIBC and PIVOTing into Intermediate Risk NMIBC

Bladder cancer remains the sixth most commonly diagnosed cancer in the United States, with an estimated 82,290 incident cases in 2023.1 Because of the persistent recurrence risk of NMIBC in a highly comorbid population, there has been an FDA-led drive towards developing novel treatment options for these patients. The following article will highlight recent advances in this disease space with a specific focus on the oncolytic adenovirus agent cretostimogene grenadenorepvec, and the registration trial in intermediate risk non-muscle invasive bladder cancer (NMIBC), PIVOT-006. 

Written by: Zachary Klaassen, MD, MSc, Wellstar MCG Health Georgia Cancer Center Augusta, Georgia, USA
References:
  1. American Cancer Society. Key Statistics for Bladder Cancer. https://www.cancer.org/cancer/types/bladder-cancer/about/key-statistics.html#:~:text=time%20of%20diagnosis-,How%20common%20is%20bladder%20cancer%3F,men%20and%204%2C550%20in%20women. Accessed on December 1, 2023.
  2. Burke JM, Lamm DL, Meng MV, et al. A first in human phase 1 study of GC0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol. 2012 Dec;188;(6):2391-2397.
  3. Packiam VT, Lamm DL, Barocas DA, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urol Oncol. 2018 Oct;36(10):440-447.

The Treatment Landscape of Metastatic Urothelial Carcinoma: First-Line Systemic Therapy in Cisplatin Eligible Patients

Introduction


Metastatic urothelial carcinoma is associated with a poor prognosis, with a median overall survival of less than two years. To date, combination platinum-based chemotherapy remains the standard of care first line treatment for these patients who are suitable for chemotherapy. This Center of Excellence article will assess criteria for determining cisplatin chemotherapy eligibility, review the landmark trials that established cisplatin-based chemotherapy as the standard of care for first-line treatment, and review recent data for avelumab maintenance therapy among patients that did not progress on first-line chemotherapy.
Written by: Zachary Klaassen, MD, MSc Associate Professor of Urology Urologic Oncologist Medical College of Georgia, Georgia Cancer Center Augusta, GA and Rashid Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, Ontario, Canada
References:
  1. Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based chemotherapy. J Clin Oncol. 2011;29: 2432-2438.
  2. Sternberg CN, Yagoda A, Scher HI, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol. 1985;133: 403-407.
  3. Sternberg CN, Yagoda A, Scher HI, et al. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer. 1989;64: 2448-2458.
  4. Bajorin DF, Dodd PM, Mazumdar M, et al. Long-term survival in metastatic transitional-cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol. 1999;17: 3173-3181.
  5. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol. 2000;18: 3068-3077.
  6. Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol. 2001;19: 2638-2646.
  7. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42: 50-54.
  8. Lee YS, Ha MS, Tae JH, et al. Gemcitabine-cisplatin versus MVAC chemotherapy for urothelial carcinoma: a nationwide cohort study. Sci Rep. 2023;13: 3682.
  9. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383: 1218-1230.
  10. Powles T, Park SH, Caserta C, et al. Avelumab First-Line Maintenance for Advanced Urothelial Carcinoma: Results From the JAVELIN Bladder 100 Trial After >/=2 Years of Follow-Up. J Clin Oncol. 2023;41: 3486-3492.
  11. Powles T, Sridhar SS, Loriot Y, et al. Avelumab maintenance in advanced urothelial carcinoma: biomarker analysis of the phase 3 JAVELIN Bladder 100 trial. Nat Med. 2021;27: 2200-2211.

Novel Targets and Treatment Developments in Metastatic Hormone Sensitive Prostate Cancer

Introduction

The last decade has seen a seismic shift in the treatment landscape of metastatic hormone sensitive prostate cancer (mHSPC). This includes several guideline and FDA approved doublet therapy options, triplet therapy options, and treatment with radiotherapy to the primary tumor:
Written by: Zachary Klaassen, MD, MSc Associate Professor of Urology Urologic Oncologist Medical College of Georgia, Georgia Cancer Center Augusta, GA and Rashid Sayyid, MD, MSc Urologic Oncology Fellow University of Toronto Toronto, Ontario, Canada
References:
  1. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2019;381(1):13-24.
  2. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021;39(20):2294-2303.
  3. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019;381(2):121-131.
  4. Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(4):323-334.
  5. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019;37(32):2974-2986.
  6. Armstrong AJ, Iguchi T, Azad AA, et al. The Efficacy of Enzalutamide plus Androgen Deprivation Therapy in Oligometastatic Hormone-sensitive Prostate Cancer: A Post Hoc Analysis of ARCHES. Eur Urol. 2023;84(2):229-241.
  7. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-351.
  8. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
  9. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20(5):686-700.
  10. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132-1142.
  11. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
  12. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial. PLoS Med. 2022;19(6):e1003998.
  13. Armenia J, Wankowicz SAM, Liu D, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018;50(5):645-651.
  14. Chung JH, Dewal N, Sokol E, et al. Prospective Comprehensive Genomic Profiling of Primary and Metastatic Prostate Tumors. JCO Precis Oncol. 2019;3.
  15. Kumar A, White TA, MacKenzie AP, et al. Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers. Proc Natl Acad Sci U S A. 2011;108(41):17087-17092.
  16. Hamid AA, Sayegh N, Tombal B, et al. Metastatic Hormone-Sensitive Prostate Cancer: Toward an Era of Adaptive and Personalized Treatment. Am Soc Clin Oncol Educ Book. 2023;43:e390166.
  17. Hamid AA, Gray KP, Shaw G, et al. Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer. Eur Urol. 2019;76(1):89-97.
  18. Velez MG, Kosiorek HE, Egan JB, et al. Differential impact of tumor suppressor gene (TP53, PTEN, RB1) alterations and treatment outcomes in metastatic, hormone-sensitive prostate cancer. Prostate Cancer Prostatic Dis. 2022;25(3):479-483.
  19. Hamid AA, Huang HC, Wang V, et al. Transcriptional profiling of primary prostate tumor in metastatic hormone-sensitive prostate cancer and association with clinical outcomes: correlative analysis of the E3805 CHAARTED trial. Ann Oncol. 2021;32(9):1157-1166.
  20. de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020.
  21. Dhiantravan N, Emmett L, Joshua AM, et al. UpFrontPSMA: a randomized phase 2 study of sequential (177) Lu-PSMA-617 and docetaxel vs docetaxel in metastatic hormone-naive prostate cancer (clinical trial protocol). BJU Int. 2021;128(3):331-342.

Novel Treatment Options for BCG Naïve Non-Muscle Invasive Bladder Cancer: Immune Priming and Immune Check Point Inhibitors

Introduction

Immune checkpoint inhibitors have emerged as a guideline-recommended first line treatment option for patients with cisplatin-ineligible, metastatic urothelial carcinoma of the bladder and as second line therapy for patients with metastatic disease progressing during, or after, platinum-based combination chemotherapy.1 Pembrolizumab, a Programmed Death-1 (PD-1) inhibitor, has been recently approved by the US Food and Drug Administration for the treatment of patients with Bacillus Calmette Guerin (BCG)-resistant non-muscle invasive bladder cancer (NMIBC), based on the results of the KEYNOTE-057 trial.2,3

Given that patients with NMIBC receiving adjuvant BCG post-TURBT have estimated risks of disease recurrence and progression of 40% and 10%, respectively,4 the BCG naïve NMIBC space may provide an opportunity to move these agents up even further along the bladder cancer disease spectrum. In this Center of Excellence article, we will summarize the current state of the evidence for ongoing trials evaluating immune check point inhibitors and other immune priming interventions in combination with BCG for the treatment of BCG naïve NMIBC.

Pembrolizumab + BCG

Previous studies have demonstrated that programmed cell death ligand 1 (PD-L1) expression is significantly increased in BCG-induced bladder granulomata of patients with BCG unresponsive disease.5 As such, it has been hypothesized that the addition of a PD-1 inhibitor, such as pembrolizumab, may overcome this potential underlying mechanism of resistance.

The combination of pembrolizumab + BCG has previously been evaluated in the setting of a phase I trial for patients with BCG unresponsive NMIBC. This combination was determined to be relatively safe, and the 13 evaluable patients had a 3-month complete response rate of 69%.6

KEYNOTE-676 is a randomized, comparator-controlled trial evaluating the efficacy and safety of pembrolizumab + BCG in patients with high-risk NMIBC (T1, CIS, high grade Ta) who underwent cystoscopy/transurethral resection of bladder tumor ≤12 weeks before randomization and had not received BCG within the preceding two years. Patients will be randomly assigned 1:1:1 to receive:

  • Pembrolizumab 400 mg IV every 6 weeks + BCG reduced maintenance (≤ 6 months)
  • Pembrolizumab 400 mg IV every 6 weeks + BCG full maintenance (≤ 18 months)
  • BCG monotherapy with BCG full maintenance

The trial schema for KEYNOTE-676 cohort B is as follows:
figure-1-BCGNaive-Immune-Priming.jpg

The primary endpoint for this trial is event-free survival, defined as the time from random assignment to the first occurrence of any of the following:

  • High-grade Ta, CIS, or any T1 disease of the bladder
  • High-risk disease (high-grade Ta, CIS, or ≥T1) of the urethra or upper tract
  • Locally advanced/metastatic disease determined by blinded independent central review
  • Death from any cause

The secondary endpoints will include complete response rate by blinded independent central review, duration of response, disease-specific survival, time to cystectomy, overall survival, and safety.7 As follows is a geographical representation of the countries currently enrolling patients in KEYNOTE-676:

figure-2-BCGNaive-Immune-Priming.jpg

Additionally, a single arm, phase II trial (NCT03504163) from the Memorial Sloan Kettering Cancer Center is evaluating the combination of BCG + pembrolizumab in patients with high-risk T1 bladder cancer, with an additional exploratory cohort of patients with upper tract disease. This study will plan to enroll 37 patients, who will receive pembrolizumab 400 mg IV at 6-week intervals (total 9 doses), with BCG (TICE strain, 50 mg) administered once weekly for 6 weeks as induction, followed by maintenance consistent with standard clinical practice. BCG will be started on week 3 after the first infusion of pembrolizumab to allow for the initial priming of T cells to further enhance the effects of BCG treatment. The primary outcome is the proportion of patients who remain free of high-grade disease recurrences at 6 months post-treatment initiation.8

Atezolizumab + BCG

BladderGATE

BladderGATE (NCT04134000) is a phase Ib-II trial evaluating the safety and efficacy of atezolizumab (anti-PD-L1) + BCG in patients with high-risk NMIBC, who are either BCG-naïve or had not received BCG in the preceding two years. Patients in this trial will receive either:

  • Induction BCG with 1 instillation every week + IV atezolizumab 1,200 mg every 3 weeks (Dose level 0)
  • Induction BCG with ½ instillation every week + IV atezolizumab 1,200 mg every 3 weeks (Dose level -1)

Following induction, BCG will be administered at weeks 13-15, 25-27, and 49-51, with atezolizumab concurrently administered for up to 1 year. Patients were accrued to each dose level in cohorts of 10 patients until the maximum tolerated dose is achieved (dose at which < 4 out of 10 patients experience dose-limiting toxicity). The interim safety results were recently presented at ASCO 2023. This analysis included 34 patients, with no dose-limiting toxicities reported in the first 10 patients included at dose level 0. The most frequent grade 3-4 adverse events were:

  • Asthenia (9%)
  • Myocarditis (3%)
  • Immune-mediated hepatitis (3%)
  • Hyponatremia (3%)
  • Encephalopathy (3%)
  • Guillain-Barre syndrome (3%)

Two patients discontinued the study treatment due to immune-mediated Grade 3 hepatitis and pneumonitis, respectively.9

ALBAN

ALBAN (AFU-GETUG 37; NCT03799835) is a phase III trial across 30 centers in France evaluating the efficacy and safety of atezolizumab given in combination with BCG versus BCG alone in patients with BCG naïve, high-risk NMIBC (T1, high-grade, and/or CIS). Eligible patients will be randomized 1:1 to:

  • Arm A: BCG alone with six weeks induction followed by three weekly maintenance instillations at 3, 6, and 12 months
  • Arm B: BCG + atezolizumab (1,200 mg IV every 3 weeks for up to 1 year)

The primary endpoint is recurrence-free survival in the intent-to-treat population, with secondary efficacy endpoints of overall survival, progression-free survival, complete response, disease worsening, quality of life, and safety outcomes. Study enrollment began in December 2018 with a target of 614 patients.10

Durvalumab + BCG

POTOMAC (NCT03528694) is an open label, multicenter, randomized trial evaluating the combination of durvalumab (anti-PD-L1) and BCG in BCG-naïve patients with high-risk NMIBC (any high-grade disease, T1, CIS, LG Ta if >3 cm, recurrent, and multifocal). This trial will randomize 1,018 patients to:

  • BCG induction + maintenance for 24 months
  • BCG induction + maintenance + durvalumab (1,500 mg every 4 weeks for 13 cycles)
  • BCG induction only (no maintenance) + durvalumab

The study design is as follows:
figure-3-BCGNaive-Immune-Priming.jpg

The primary study endpoint is disease-free survival, with secondary endpoints including the proportion of patients alive and disease-free at 24 months, 5-year overall survival, pharmacokinetics, immunogenicity, safety, tolerability, and health-related quality of life.11

Sasanlimab + BCG

Sasanlimab is an anti-PD-1 monoclonal antibody that has demonstrated an acceptable safety profile and promising clinical activity in patients with locally advanced or metastatic urothelial carcinoma, within the context of a phase 1 trial.12 The phase 3 CREST study (NCT04165317) Cohort A will evaluate subcutaneous sasanlimab in patients with BCG naive NMIBC. Patients in this cohort will be randomized to one of three arms:

  • Arm A: Sasanlimab + BCG induction + maintenance
  • Arm B: Sasanlimab + BCG induction only (Discontinued August 31, 2022 per the sponsor)
  • Arm C: BCG induction + maintenance

This trial will assess for between-arm differences in event-free, disease-specific, and overall survivals, complete response rate, adverse events/safety profile, and health-related quality of life.13 Of note, CREST Cohort B is enrolling patients with BCG-unresponsive NMIBC.

Immune Priming: Intradermal BCG

The PRIME trial (SWOG S1612) is evaluating whether intradermal BCG inoculation may potentiate the immune effects of subsequent intravesical BCG instillations. This hypothesis was recently tested in a single arm trial that demonstrated that percutaneous BCG administered 21 days prior to intravesical instillation in patients with high-risk NMIBC boosted BCG-specific immunity at 3 months and increased the activation status of in vitro expanded circulating NK and γδ T cells and their cytotoxicity against bladder cancer cells.14

In the PRIME trial, the Tokyo BCG strain is being used for both intradermal inoculation and intravesical instillation in a three-arm design with TICE strain BCG also used as a standard of care comparator. This study was designed to test:

  • The comparitive superiority between intravesical Tokyo strain BCG when combined with intradermal inoculation as compared to intravesical alone (arms 2 and 3)
  • The non-inferiority of intravesical Toyko strain alone to intravesical TICE strain (arms 1 and 2).
    • TICE strain is currently the only strain that is FDA approved and in production in the USA (Armond-Frappier and Connaught are also FDA approved, but not currently in production). As such, if the Tokyo strain is found to be non-inferior to TICE, this may facilitate its subsequent FDA approval and increased the availability of additional BCG strains during the current shortage

The study design is as follows:
figure-4-BCGNaive-Immune-Priming.jpg

This trial has now fully accrued and is awaiting readout in the nearby future.

Conclusions

Numerous ongoing trials are evaluating the combination of BCG and an immune checkpoint inhibitor for patients with BCG naïve NMIBC. By inhibiting the PD-1/PD-L1 axis, it is hypothesized that these agents may help overcome underlying mechanisms of resistance inherent to BCG-resistant strains, and thus improve on the historic recurrence and progression rates observed with BCG treatment alone. Many of these trials have completed accrual, and we await the results of these combinatory trials in the upcoming years.

Published August 2023
Written by: Rashid K. Sayyid, MD, MSc, University of Toronto, Toronto, ON & Zachary Klaassen, MD, MSc, Medical College of Georgia, Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer. https://uroweb.org/guidelines/non-muscle-invasive-bladder-cancer. Accessed on Aug 6, 2023.
  2. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-bcg-unresponsive-high-risk-non-muscle-invasive-bladder-cancer. Accessed on Aug 6, 2023.
  3. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-30.
  4. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  5. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7–H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer. 2007;109(8):1499-505
  6. Alanee S, Sana S, El-Zawahry A, et al. Phase I trial of intravesical Bacillus Calmette-Guérin combined with intravenous pembrolizumab in recurrent or persistent high-grade non-muscle-invasive bladder cancer after previous Bacillus Calmette-Guérin treatment. World J Urol. 2021;39(10):3807-13.
  7. Kamat AM, Shariat S, Steinberg GD, et al. Randomized comparator-controlled study evaluating efficacy and safety of pembrolizumab plus Bacillus Calmette-Guérin (BCG) in patients with high-risk nonmuscle-invasive bladder cancer (HR NMIBC): KEYNOTE-676 cohort B. J Clin Oncol. 2022;40(Suppl 6): TPS597
  8. ClinicalTrials.gov - Pembrolizumab (MK-3475) and Bacillus Calmette-Guérin (BCG) as First-Line Treatment for High-Risk T1 Non-Muscle-Invasive Bladder Cancer (NMIBC) and High-Grade Non-Muscle-Invasive Upper Tract Urothelial Carcinoma (NMI-UTUC)].  
  9. Castellano D, de Velasco G, Carretero-Gonzalez A, et al. Atezolizumab + intravesical BCG (bacillus Calmette-Guerin) upfront combination in high risk non–muscle- invasive bladder cancer (NMIBC) patients: Safety interim report of BladderGATE phase I-II study. J Clin Oncol. 2023;41(Supp 16):e16590.
  10. Roupret M, Neuzillet Y, Bertaut A, et al. ALBAN: An open label, randomized, phase III trial, evaluating efficacy of atezolizumab in addition to one year BCG (Bacillus Calmette-Guerin) bladder instillation in BCG-naive patients with high-risk nonmuscle invasive bladder cancer (AFU-GETUG 37). J Clin Oncol. 2019;37(Suppl 15):TPS4589.
  11. De Santis M, Abdrashitov R, Hegele A, et al. A phase III, randomized, open-label, multicenter, global study of durvalumab and bacillus calmette-guérin (BCG) versus BCG alone in high-risk, BCG-naïve non-muscle-invasive bladder cancer (NMIBC) patients (POTOMAC). J Clin Oncol. 2019;37(Suppl 7):TPS500.
  12. Shore ND, Powles T, Bedke J, et al. A phase 3 study of the subcutaneous programmed cell death protein 1 inhibitor sasanlimab as single agent for patients with bacillus Calmette-Guérin, unresponsiv,e high-risk, non-muscle invasive bladder cancer: CREST Study Cohort B. J Clin Oncol. 2022;40(Suppl 16):40.
  13. ClinicalTrials.gov. A Study of Sasanlimab in People With Non-muscle Invasive Bladder Cancer (CREST). https://classic.clinicaltrials.gov/ct2/show/NCT04165317. Access on Aug 6, 2023.
  14. Ji N, Mukherjee N, Morales EE, et al. Percutaneous BCG enhances innate effector antitumor cytotoxicity during treatment of bladder cancer: a translational clinical trial. Oncoimmunology. 2019;8(8):1614857.

Novel Treatment Targets in the Metastatic Castrate-Resistant Prostate Cancer Disease Space

Introduction

Since the United States Food and Drug Administration (FDA) approval of mitoxantrone in 19961 and docetaxel in 20042 for the treatment of patients with metastatic castrate-resistant prostate cancer, we have witnessed the approval of numerous additional agents/combinations in this disease space:

Written by: Rashid K. Sayyid, MD MSc University of Toronto Toronto, ON & Zachary Klaassen, MD MSc Georgia Cancer Center Wellstar MCG Health Augusta, Georgia
References:
  1. Tannock IF, Osoba D, Stockler MR, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol. 1996:14(6):1756-1764.
  2. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.
  3. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
  4. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet. 2010;376(9747):1147-1154.
  5. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.
  6. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148.
  7. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
  8. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
  9. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-433.
  10. Center for Drug Evaluation and Research. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. U.S. Food and Drug Administration.
  11. Abida W, Patnaik A, Campbell D, et al. Rucaparib in Men with Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. J Clin Oncol. 2020;38(32):3763-3772.
  12. de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091-2102.
  13. Hofman MS, Emmett L, Sandhu S, et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): A randomized, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.
  14. Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385(12):1091-1103.
  15. Clarke N, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evidence. 2022.EVIDoa2200043.
  16. Agarwal N, Azad A, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. The Lancet. 2023;402(10398):291-303.
  17. George DJ, Sartor O, Miller K, et al. Treatment Patterns and Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer in a Real-world Clinical Practice Setting in the United States. Clin Genitourin Cancer. 2020;18(4):284-94.
  18. Koivisto P, Kononen J, Palmberg C, et al. Androgen Receptor Gene Amplification: A Possible Molecular Mechanism for Androgen Deprivation Therapy Failure in Prostate Cancer. Cancer Res. 1997;57(2):314-9.
  19. Henzler C, Li Y, Yang R, et al. Truncation and constitutive activation of the androgen receptor by diverse genomic rearrangements in prostate cancer. Nat Commun. 2016;7:13668.
  20. Pachynski RK, Iannotti N, Laccetti AL, et al. Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(Suppl 6):177.
  21. Laccetti AL, Chatta GS, Iannotti N, et al. Phase 1/2 study of EPI-7386 in combination with enzalutamide (enz) compared with enz alone in subjects with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(Suppl 6):179.
  22. Desai K, Serritella AV, Stadler WM, et al. Phase I trial of enzalutamide (Enz) plus the glucocorticoid receptor antagonist relacorilant (Rela) for patients with metastatic castration resistant prostate cancer. J Clin Oncol. 2023;41(Suppl 6):5062.
  23. Fizazi K, Cook N, Barthelemy P, et al. Phase 1 results of the ODM-208 first-in-human phase 1-2 trial in patients with metastatic castration-resistant prostate cancer (CYPIDES). J Clin Oncol. 2022;40(Suppl 6):18.
  24. Smith MR, Agarwal N, Todenhofer T, et al. CYCLONE 2: A phase 2/3, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2022;40(Suppl 6):198.
  25. Dorff TB, Blanchard S, Martirosyan H, et al. Final results from phase I study of PSCA-targeted chimeric antigen receptor (CAR) T cells in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(Suppl 6):5019.
  26. Sandhu S, Joshua AM, Emmett L, et al. LuPARP: Phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(Suppl 6):5005.
  27. Kostos LK, Buteau JP, Kong G, et al. LuCAB: A phase I/II trial evaluating cabazitaxel in combination with [177Lu]Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2023;41(Suppl 6):TPS278.
  28. Teiluf K, Seidl C, Blechert B, et al. α-Radioimmunotherapy with 213Bi-anti-CD38 immunoconjugates is effective in a mouse model of human multiple myeloma. Oncotarget. 2015;6:4692-4703.
  29. Ma J, Li L, Liao T, Fong W, Zhang C. Efficacy and Safety of 225Ac-PSMA-617-Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis. Front Oncol. 2022;12:796657.
  30. Nauseef JT, Sun MP, Thomas C, et al. A phase I/II dose-escalation study of fractionated 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC) in patients with prior treatment with 177Lu-PSMA. J Clin Oncol. 2023;41(Supp 6):TPS288.

Novel Treatment Options for BCG Naïve Non-Muscle Invasive Bladder Cancer: Intravesical Chemotherapy

Introduction

Bacillus Calmette Guerin (BCG) is currently guideline-recommended in the adjuvant setting for patients with intermediate or high-risk non-muscle invasive bladder cancer (NMIBC).1 This is based on the results of numerous randomized clinical trials and meta-analyses demonstrating its ability to reduce the rates of disease recurrence and progression, compared to transurethral resection of bladder tumor (TURBT) alone or other adjuvant therapies.2-5

Written by: Rashid K. Sayyid, MD, MSc University of Toronto Toronto, ON & Zachary Klaassen, MD, MSc Medical College of Georgia Augusta, Georgia, USA
References:
  1. EAU Guidelines: Non-muscle-invasive Bladder Cancer. https://uroweb.org/guidelines/non-muscle-invasive-bladder-cancer. Accessed on Aug 5, 2023.
  2. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guerin, and bacillus Calmette-Guerin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol. 2010;57(5):766-73.
  3. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Review. 2020;1(1):CD011935.
  4. Malmstrom PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur Urol. 2009;56(2):247-56.
  5. Bohle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol. 2003;169(1):90-5.
  6. Oresta B, et al. Sci Transl Med. Jan 6;13(575):eaba6110 Clinical trial information: EudraCT 2021-003751-42_studio ICH-013 (MMC).
  7. Di Stasi SM, Giannantoni A, Giurioli A, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol. 2006;7:43-51.
  8. Solsona E, Madero R, Chantada V, et al. Sequential combination of mitomycin C plus bacillus Calmette-Guérin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial. Eur Urol. 2015;67(3):508-16.
  9. Kaasinen E, Wijkstrom H, Rintala E, et al. Seventeen-year follow-up of the prospective randomized Nordic CIS study: BCG monotherapy versus alternating therapy with mitomycin C and BCG in patients with carcinoma in situ of the urinary bladder. Scand J Urol. 2016;50(5):360-8.
  10. De Nunzio C, Leonardo C, Carbone A, et al. MP63-12 THE EFFECTS OF SEQUENTIAL MITOMYCIN AND BACILLUS CALMETTE-GUÉRIN TREATMENT VERSUS BACILLUS CALMETTE-GUÉRIN MONOTHERAPY IN PATIENTS WITH HIGH-RISK NON-MUSCLE INVASIVE BLADDER CANCER: MITO-BCG (EUDRACT-2017-004540-37). J Urol. 2023;209(Suppl 4):e876.
  11. Jagannath C, Lindsey DR, Dhandayuthapani S, et al.. Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells. Nat Med. 2009;15:267–76.
  12. Ji N, Mukherjee N, Reyes RM, et al. Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study. J Immunother Cancer. 2021;9(3):e001941.
  13. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Nonmuscle Invasive Bladder Cancer. J Urol. 2020;203(5):902-9.
  14. McElree IM, Steinberg RL, Mott SL, et al. Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non–Muscle-Invasive Bladder Cancer. JAMA Netw Open. 2023;6(2):e230849.
  15. Guerrero-Ramos F, Gonzalez-Padilla DA, Gonzalez-Diaz A, et al. Recirculating hyperthermic intravesical chemotherapy with mitomycin C (HIVEC) versus BCG in high-risk non-muscle-invasive bladder cancer: results of the HIVEC-HR randomized clinical trial. World J Urol. 2022;40(4):999-1004.

The Current State of Treatment Implementation for mCRPC in North America

Introduction

There have been significant advances in the metastatic castrate-resistant prostate cancer (mCRPC) treatment landscape with the emergence and approval of numerous agents in this disease space.
Written by: Rashid Sayyid, MD MSc University of Toronto Toronto, ON & Zachary Klaassen, MD MSc Georgia Cancer Center Wellstar MCG Health Augusta, GA
References:
  1. Freedland SJ, Davis M, Epstein AJ, et al. Real-world treatment patterns and overall survival among men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) in the US Medicare population. Prostate Cancer Prostatic Dis. 2023.
  2. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate. Accessed on October 29, 2023.
  3. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer. Accessed on October 29, 2023.
  4. FDA D.I.S.C.O. Burst Edition: FDA approval of Lynparza (olaparib), with abiraterone and prednisone, for BRCA-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-lynparza-olaparib-abiraterone-and-prednisone-brca-mutated#:~:text=On%20May%2031%2C%202023%2C%20the,FDA%2Dapproved%20companion%20diagnostic%20test.. Accessed on October 29, 2023.
  5. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate. Accessed on October 29, 2023.
  6. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer. Accessed on October 29, 2023.
  7. Swami U, Aggarwal H, Zhou M, et al. Treatment Patterns, Clinical Outcomes, Health Care Resource Utilization and Costs in Older Patients With Metastatic Castration-Resistant Prostate Cancer in the United States: An Analysis of SEER-Medicare Data. Clin Genitourin Cancer. 2023;21(5):517-529.
  8. Shayegan B, Wallis CJD, Malone S, et al. Real-world use of systemic therapies in men with metastatic castration resistant prostate cancer (mCRPC) in Canada. Urol Oncol. 2022;40(5):192.e1-192.e9.
  9. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512.
  10. Khalaf DJ, Annala M, Taavitsainen S, et al. Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial. Lancet Oncol. 2019;20(12):1730-1739.
  11. de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091-2102.
  12. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N Engl J Med. 2023;388:719-732.
  13. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.
  14. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.
  15. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet. 2010;376(9747):1147-1154.
  16. Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385(12):1091-1103.
  17. Hofman MS, Emmett L, Sandhu S, et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): A randomized, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.
  18. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med. 2019;381(26):2506-2518.

The Path Forward for Telehealth in Medicare

The COVID-19 pandemic brought about a rapid expansion of telehealth services to ensure that patients were able to obtain necessary medical care without exposure to illness. Prior to this point, Medicare was very hesitant to cover telemedicine given lack of evidence regarding quality and cost, as well as effects on outcomes. As the Public Health Emergency (PHE) ended in May 2023, Congress turned to the Medicare Payment Advisory Commission (MedPAC) for an evaluation of the current state of telehealth services, and for recommendations on how to provide payment for telehealth services in the future.

The Current State of Treatment Implementation for Metastatic Hormone Sensitive Prostate Cancer in North America

Introduction

Since 1941, the backbone of treatment for advanced prostate cancer has been androgen deprivation therapy (ADT). However, treatment advancement remained relatively stagnant until the last decade, when we saw the emergence of several doublet and triplet therapy options, using ADT as the backbone of treatment, leading to an overall survival (OS) advantage versus ADT alone.

Figure 1: The current landscape of FDA combination approvals in Metastatic Hormone Sensitive Prostate Cancer (mHSPC)1-12 
figure-1-mHSPC-current-state.jpg
Thus, this has changed the standard of care for treatment intensification for these men. This article will focus a discussion on the implementation of treatment for Metastatic Hormone Sensitive Prostate Cancer (mHSPC) in North America, specifically highlighting the landscape and challenges of treatment intensification, and the importance of disease volume and timing of metastasis for selecting the optimal treatment in the mHSPC disease space.

The Enigma of (Lack of) Treatment Intensification

Despite the approval and availability of multiple mHSPC treatment intensification strategies, there remains a clear underutilization of these combination strategies in real-world practice. The following discussion will highlight several of the key studies looking at contemporary treatment intensification across several North American jurisdictions.

Ryan et al. reported treatment utilization trends of mHSPC patients between January 2014 and July 2019 from two large U.S databases: (i) Optum’s de-identified Clinformatics Data Marta Database (COM/MA), which includes claims from commercial and Medicare Advantage plans for 13 million people across the United States and (ii) Centers for Medicare & Medicaid Services-sourced Medicare Fee-for-Service (FFS) Research Identifiable Files Sample.13  A total of 19,841 mHSPC patients (6,517 COM/MA and 13,324 Medicare-FFS) were identified with a median follow up of 9.6 – 10.5 months. Notably, 38% of COM/MA and 48% of Medicare-FFS patients remained untreated or deferred treatment during the study period, whereas 45% and 46%, respectively, were treated with first line ADT monotherapy only. Abiraterone acetate or docetaxel was used as first line therapy in 13% (COM/MA) and 2%

(Medicare-FFS) of patients. Approximately 43% and 38% of patients, respectively, only received ADT monotherapy (with or without a first-generation androgen signaling inhibitors) during the entire mHSPC period despite the availability of other more potent therapies. It is important to note that apalutamide and enzalutamide were added to evidence-based guidelines as mHSPC treatments after the end of the study period (July 31, 2019) and were not considered as mHSPC therapy in the current study. When stratified by year of index date, in the COM/MA database, treatment with first line ADT monotherapy decreased numerically from 48% to 43% among patients diagnosed with mHSPC in 2015 – 2017 versus 2018 – 2019. While the overall use of abiraterone or docetaxel remained similar in the two periods (12% - 14%), the relative use of abiraterone acetate increased among patients diagnosed in 2018 - 2019 (10%) versus 2015 - 2017 (5%), whereas the use of docetaxel decreased in 2018 - 2019 (4%) compared with 2015 – 2017 (7%).

Figure 2: First line therapy in patients with mHSPC by year of index data in the Clinformatics Data Marta Database13 
figure-2-mHSPC-current-state.jpg
Analysis from the Veterans Health Administration (VHA) database was reported by Freedland et al.14  for 1,395 mHSPC patients treated between April 2013 and March 2018. Across the five-year study period, 63% of patients received ADT alone as first line treatment while ADT + non-steroidal anti-androgen was used in 24%, ADT + docetaxel in 8%, and ADT + abiraterone for the remaining 5%. Treatment trends over time did demonstrate an overall decrease in ADT only (66% to 60%) or ADT + non-steroidal anti-androgen (31% to 17%) utilization between 2014 and 2017-2018, with a corresponding increase in utilization of ADT+ docetaxel (3% to 9%) and ADT + abiraterone (1% to 15%). Nonetheless, despite increased adoption of treatment intensification in VHA mHSPC patients, there remains a clear underutilization of appropriate treatment intensification.

Figure 3: Treatment trends over time among patients with mHSPC in the Veterans Health Administration14
figure-3-mHSPC-current-state.jpg
A comparison of patients in the four treatment groups demonstrated that patients receiving ADT and docetaxel, compared to the ADT only cohort, were younger (65.8 versus 73.4 years) and had fewer comorbidities (National Cancer Institute comorbidity score 1.1 versus 1.5), but had greater disease burden in terms of higher PSA (338.1 ng/ml versus 256.4 ng/ml) and overall metastatic burden. ADT + abiraterone patients were older (75.3 versus 73.4 years), generally had fewer cardiovascular comorbidities and lower PSA (238.3 versus 256.5 ng/ml) but had increased metastasis (other sites including bone: 80% versus 73%).

A combined analysis from the VHA and Medicare database was presented at ESMO 2022. The authors identified 33,641 and 5,561 men in the Medicare and VA cohorts, respectively. Similar to the prior report by Freedland et al.,    14  the authors demonstrated that the proportion of patients receiving treatment intensification with novel hormonal therapy or docetaxel increased over time, although by 2018/2019, still less than one third of patients with mHSPC received first line ADT plus docetaxel or ADT plus a novel hormonal agent.

Figure 4: Utilization of first line treatment intensification over time for mHSPC patients in the VHA and Medicare databases
figure-4-mHSPC-current-state.jpg
While there were changes in treatment approaches between 2010 and 2014, the authors did not find any changes in overall survival in 2012–2014 compared with 2010–2011, though there was improvement in overall survival by 12% and 15% in the Medicare and VA cohorts, respectively, in 2015–2018/2019 versus 2010–2011, after adjusting for baseline characteristics, suggesting that diffusion of these intensified treatment approaches provides a population-level survival benefit.

Figure 5: Overall survival for mHSPC patients in the VHA and Medicare databases
figure-5-mHSPC-current-state.jpg
A Medicare analysis of treatment intensification trends among racial minorities was presented by Freedland et al. at ASCO 2021. Compared to White, non-Hispanic men, Black men were less likely to receive treatment intensification (ADT + docetaxel or novel hormonal therapy) during 2010-2014 (2.6% versus 3.2%), 2015-2016 (8.7% versus 10.4%), and 2017 (14.2% versus 15.1%).

Using provincial data from Ontario, Canada, Wallis et al.15  identified 3,556 patients diagnosed with de novo mHSPC between 2014 and 2019. Of note, 78.6% of patients received ADT alone (with or without an anti-androgen), 11.2% received treatment intensification with docetaxel, 1.5% received abiraterone acetate and prednisone, with the remaining 8.7% receiving a “non-ADT” regimen. Patients receiving docetaxel were comparatively younger (mean age 72.6 years) and healthier (mean Charlson Comorbidity Index score of 0.15). The median PSA at diagnosis was lower among patients who received conventional ADT (88 ng/mL) compared with ADT intensification regimens (121 ng/mL and 152 ng/mL for the abiraterone and docetaxel cohorts, respectively). A time-stratified analysis representing the uptake of ADT intensification regimens before and after the pivotal 2017 LATITUDE trial,8  demonstrated that abiraterone acetate plus prednisone prescriptions increased from 0.5% to 3% in the pre- versus post-LATITUDE period, respectively, whereas docetaxel treatment dropped from 12% to 10%. As was reported by Ryan et al.13, these data suggest that the pivotal data from LATITUDE and STAMPEDE resulted in a substitution of intensification approach (from docetaxel to abiraterone) rather than a broadening of the patient population receiving treatment intensification.

Given the underwhelming utilization of treatment intensification for mHSPC patients in the real-world setting, barriers to improved adoption need to be further understood. At ASCO 2022, Freedland et al. provided the first granular assessment as to reasons for or against treatment intensification. This study examined data from medical charts of patients initiating mHSPC treatment from July 2018 to November 2021 based on a retrospective review of multiple US academic/community practices. This was a survey of oncologists and urologists who treated these patients to provide reasons for treatment choices, including PSA goals and explicit reasons for not prescribing novel hormonal agents. This analysis included 621 patients who were treated by 65 oncologists and 42 urologists. In the first line setting, most mHSPC patients received ADT ± non-steroidal anti-androgen alone (69%), while treatment intensification rates with ADT + novel hormonal agent (26%) or ADT + chemohormonal therapy (4%) were low. Following the initial treatment course, an additional 166 patients (27%) received subsequent treatment intensification while still castration-sensitive, prior to progression to castration resistant disease.

When the physicians were queried about reasons for not using novel hormonal agents, the most frequently cited reasons were:

  1. “Novel hormonal therapy would need to have a better/more tolerable side effect profile/fewer adverse events than my chosen regimen” (38%)
  2. “I would need to have seen clinical trial evidence of survival improvements on novel hormonal therapies including a wider range of prostate cancer patients” (31%)
  3. “Novel hormonal therapies would need to be reimbursed by patients’ insurance” (26%)

Figure 6: Reasons given by providers for not using novel hormonal therapy
figure-6-mHSPC-current-state.jpg
Regarding treatment goals for PSA response, physicians more frequently reported a relative reduction than an absolute PSA reduction (85% versus 51%). Oncologists considered a median PSA reduction of 50% (IQR 25-75%) adequate versus 75% (IQR 50-90%) among urologists. Urologists were more likely to utilize treatment intensification in the first line setting or subsequently in patients who were still castration-sensitive (p < 0.01). Furthermore, physicians who aimed for deeper PSA reductions of 75-100% were more likely (OR: 1.63, p = 0.034) to provide treatment intensification in the first-line setting compared with physicians with less aggressive PSA goals (0 – 49%). The authors concluded that physician survey results suggest that perceptions of tolerability and lack of efficacy and financial considerations affect novel hormonal therapy use. In practice, non-guideline driven PSA reduction goals are associated with low rates of treatment intensification, and these results clearly demonstrate the need for further medical education.

Treating Implementation: Using Disease Volume and Timing of Metastasis to Guide Treatment Selection

Patients with mHSPC at the time of diagnosis are defined as having de novo or synchronous metastatic disease. Additionally, there is a subset of men initially diagnosed with non-metastatic disease, many of whom had received prior definitive local treatment, who will have progression to a metastatic state prior to development of castration resistance; this is known as metachronous mHSPC. This distinction between synchronous (i.e. de novo) and metachronous presentations is of utmost clinical importance given the known differences in underlying genomic mutational profiles and prognoses, influencing the subsequent choice of treatment intensification.16  These two cohorts can be further subdivided based on the volume of metastatic disease at presentation: low and high volumes. The CHAARTED high-volume criteria have been widely adopted in clinical practice, with high volume patients defined as follows: presence of visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis.17 

As such four distinct subgroups become clinically relevant (median OS per CHAARTED and GETUG-15 among men receiving ADT alone, i.e., the control groups in these trials):

  1. Synchronous and high volume: 3 years
  2. Synchronous and low volume: 4.5 year
  3. Metachronous and high volume: 4.5 years
  4. Metachronous and low volume: ~8 years

While early, aggressive treatment intensification with triplet regimens, with or without primary radiotherapy, may seem attractive in this cohort of patients to maximize survival outcomes, the reality is that such “maximal” treatment intensification is unnecessary in the majority of these patients. Furthermore, treatment toxicity, both from a pathophysiologic and financial standpoint, must be considered in these patients. As such, a nuanced approach to the treatment of such patients, guided by the aforementioned four presentations (synchronous high volume, synchronous low volume, metachronous high volume, and metachronous low volume) is needed. Arguably, over the next several years, particularly until reliable biomarkers become available, this will be how most clinicians implement treatment for mHSPC patients in North America.

Synchronous High Volume mHSPC

Based on the results from PEACE-118  and ARASENS10, as well as subgroup analysis from ENZAMET3, it appears that this patient cohort, particularly those who are chemotherapy-fit, are most likely to benefit from triplet therapy with docetaxel + androgen receptor pathway inhibitor (ARPI) + ADT.

ADT + Docetaxel + Abiraterone

The PEACE-1 trial18  employed a 2x2 design to assess, (separately and combined) the impact of the addition of abiraterone + prednisone +/- radiation therapy to standard of care therapy in men with de novo mHSPC. Among patients with high volume disease, the addition of abiraterone + prednisone to standard of care resulted in a 53% improvement in rPFS with a median rPFS of 1.6 years in the standard of care arm and 4.1 years in the standard of care plus abiraterone + prednisone arm (HR: 0.47, 95% CI: 0.36 to 0.60). The addition of abiraterone + prednisone to standard of care in patients with low volume disease still resulted in a 42% improvement in rPFS with median rPFS of 2.7 years on the standard of care arm versus not yet reached in the standard of care plus abiraterone + prednisone + ADT arm (HR: 0.58, 95%: CI 0.39 to 0.87). With regards to overall survival in patients with a de novo presentation, a benefit was seen mainly in those with high-volume disease (median overall survival 5.1 versus 3.6 years; HR: 0.77, 95% CI: 0.62 to 0.96), with a marginal, non-significant improvement in those low volume de novo disease (median overall survival not reached; HR: 0.93, 95% CI: 0.69 to 1.28). The overall survival data is immature for the low volume patients due to a small number of events.

Notably, 81% of patients in the ADT plus docetaxel standard of care control arm subsequently received a next generation hormonal therapy at the time of disease progression. This suggests that early intensification with the addition of abiraterone + prednisone to standard of care therapy results in improvement in rPFS and OS compared to sequential therapy.

ADT + Docetaxel + Darolutamide

The ARASENS trial evaluated the addition of darolutamide to standard of care therapy consisting of ADT + docetaxel versus ADT + docetaxel alone.10  Darolutamide + ADT + docetaxel prolonged overall survival for high volume mHSPC (HR 0.69, 95% CI 0.57-0.82).19 

Figure 7: Overall survival of darolutamide + ADT + docetaxel vs ADT + docetaxel for high volume disease patients in the ARASENS trial
figure-7-mHSPC-current-state.jpg

ADT + Enzalutamide vs ADT

While the ENZAMET trial was designed to compare the combination of ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen, the study design allowed for previous/concurrent use of docetaxel. In this trial, six cycles of docetaxel were given to 65% of patients in the enzalutamide group versus 76% in the standard of care group. Updated results of the ENZAMET trial were published in 20234, with survival outcomes stratified by disease volume (high versus low) and presentation (synchronous versus metachronous). Based on these subgroup analyses, patients with synchronous, high-volume mHSPC had a clinical benefit, albeit not statistically significant, for ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen whether they were planned to have docetaxel (HR: 0.79, 95% CI: 0.57 to 1.10) or in the intention to treat analysis (HR: 0.70, 95% CI: 0.47 to 1.04).

Figure 8: Overall survival in ENZAMET for patients with synchronous high volume mHSPC
figure-8-mHSPC-current-state.jpg
Results from these three trials provide strong evidence to support the use of a triplet regimen approach in patients with synchronous, high volume mHSPC. It bears note, however, that routine use of docetaxel may not be feasible in patients with contraindications to taxane therapy, including poor performance status, blood dyscrasias, and peripheral neuropathy. Such patients would likely benefit from ARPI addition to standard ADT. 

Synchronous Low Volume mHSPC

ADT + Docetaxel + ARAT

For patients with low volume disease, there appears to be a potential late clinical benefit to triplet therapy of ADT + docetaxel + darolutamide, however, with few events and additional follow-up time likely required, there is no statistically significant benefit at this point (HR: 0.68, 95% CI: 0.41 to 1.13)

Figure 9: Overall survival of darolutamide + ADT + docetaxel vs ADT + docetaxel for low volume disease patients in ARASENS
figure-9-mHSPC-current-state.jpg
Similarly, for patients treated in the ENZAMET trial with low volume synchronous disease, there was no benefit for ADT + enzalutamide versus ADT + standard nonsteroidal antiandrogen for those planned for docetaxel (HR: 0.57, 95% CI: 0.29 to 1.12). 

Figure 10: Overall survival of enzalutamide + ADT + docetaxel vs ADT + docetaxel + non-steroidal anti-androgen for synchronous low volume disease patients
figure-10-mHSPC-current-state.jpg
ARATs + ADT

There is consistent evidence across all major published phase III trials to support an overall survival benefit to the addition of an ARPI to ADT in patients with synchronous low-volume disease. This is reflected, as follows:

  • LATITUDE (abiraterone + ADT versus ADT alone; all de novo): HR 0.72, 95% CI 0.47 to 1.109
  • STAMPEDE (abiraterone + ADT versus ADT alone; >90% de novo): HR 0.64, (95% CI 0.42 to 0.96)10
  • TITAN (apalutamide + ADT versus ADT alone; 10% prior docetaxel): HR 0.52, 95% CI 0.35 to 0.7911
  • ENZAMET (enzalutamide + ADT versus non-steroidal antiandrogen + ADT): HR 0.58, 95% CI 0.32 to 1.04    4 
  • ARCHES (enzalutamide + ADT versus ADT alone; 18% prior docetaxel): HR 0.66, 95% CI 0.43 to 1.0312

As such, ARPI addition to ADT has become the backbone of any treatment approach in patients with synchronous, low volume prostate cancer.

Primary Radiotherapy for synchronous, low volume mHSPC patients

Beyond systemic treatment intensification, local prostate-directed therapy may allow for local treatment intensification. While a surgical approach using radical prostatectomy has been described, high quality data are limited to radiotherapy. Of note, the SWOG 1802 trial is accruing patients with a surgical arm in the setting of mHSPC to further assess the impact of cytoreductive prostatectomy in this disease space. Three trials to date have evaluated the role of local radiotherapy in the prostate in patients with mHSPC.

STAMPEDE (Arm H) was an open label, randomized controlled phase III trial of 2,061 men at 117 hospitals across Switzerland and the UK.11  This trial randomized patients with de novo mHSPC in a 1:1 fashion to standard of care + radiotherapy or standard of care alone. Men allocated to radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomization. The primary outcome of this trial was overall survival. Subgroup analysis by metastatic volume (CHAARTED criteria) was planned a priori. Median follow up for STAMPEDE Arm H was 37 months, median patient age was 68 years, and median PSA was 97 ng/ml. 18% of patients received early docetaxel. In the overall cohort, radiotherapy improved failure-free survival (HR: 0.76, 95% CI:0.68 to 0.84) but not overall survival (HR: 0.92, 95% CI: 0.80 to 1.06). However, when stratified by metastatic burden, overall survival benefits were seen in the low volume group (HR: 0.68, 95% CI: 0.52 to 0.90) with restricted mean survival time improved by 3.6 months from 45.4 to 49.1.11  

Figure 11: Overall survival in low metastatic burden patients with mHSPC and radiotherapy to the prostate primary in STAMPEDE Arm H
figure-11-mHSPC-current-state.jpg
HORRAD was a multicenter prospective randomized clinical trial of 432 patients with previously untreated, de novo mHSPC at 28 centers across The Netherlands between November 2004 and September 2014.    20  All eligible patients had a PSA >20 ng/ml and documented bone metastases on bone scan. Patients were randomized in a 1:1 fashion to either ADT with EBRT or ADT alone, with a primary endpoint of overall survival. The median PSA was 142 ng/mL and over a median follow up of 47 months, the median overall survival was non-significantly different at 45 months in the radiotherapy + ADT arm compared to 43 months in ADT alone arm (HR: 0.90, 95% CI: 0.70 to 1.14). 

Results of the efficacy and safety of prostate radiotherapy for patients with low volume, de novo mHSPC from the PEACE-1 trial were recently presented at ASCO 2023. The addition of prostate radiotherapy to standard of care + abiraterone was associated with significant rPFS benefits (median 7.5 versus 4.4 years, p=0.02). Conversely, addition of radiotherapy to standard of care therapy alone was not associated with rPFS benefits (median 2.6 versus 3.0 years; HR: 1.11, 95% CI: 0.67 to 1.84, p=0.61).
figure-12-mHSPC-current-state.jpg
The addition of prostate radiotherapy to either standard of care alone or standard of care therapy + abiraterone was not associated with overall survival improvements. In the standard of care + abiraterone arms, addition of prostate radiotherapy was associated with modest, non-significant OS benefits (HR: 0.77, 95% CI: 0.51 to 1.16, p=0.21). Similarly, addition of prostate radiotherapy to standard of care alone did not improve overall survival (HR: 1.18, 95% CI: 0.81 to 1.71, p=0.39).
figure-13-mHSPC-current-state.jpg
Interestingly, addition of prostate radiotherapy to standard of care +/- abiraterone in the low-volume cohort was associated with significant improvements in the time to serious genitourinary events (p=0.0006). This overall benefit was consistent irrespective of whether patients had prostate radiotherapy added to standard of care + abiraterone (p=0.003) or standard of care therapy alone (p=0.048). 

The majority of patients with synchronous, low volume mHSPC benefit from early systemic treatment intensification with ARPI addition to ADT. Such patients should also be offered primary radiotherapy to the prostate gland in the appropriate clinical settings. 

Metachronous High Volume mHSPC

Docetaxel + ARPI + ADT

Given that the PEACE-1 trial included patients with de novo mHSPC only, ARASENS and ENZAMET provide the available data to assess the benefit of triplet therapy in this mHSPC subgroup. In ARASENS, the overall survival for patients with high volume mHSPC had a prespecified subgroup analysis for assessing recurrent (metachronous) disease (n =117) with a clinical benefit, but no statistically significant benefit (HR: 0.70, 95% CI: 0.39 to 1.24). In the ENZAMET trial, there was no benefit to treatment intensification for triplet therapy (HR: 1.18, 95% CI: 0.66 to 2.11).

Figure 14: Overall survival of enzalutamide + ADT + docetaxel vs ADT + docetaxel + non-steroidal anti-androgen for metachronous high volume disease patients in ENZAMET
figure-14-mHSPC-current-state.jpg

ARPI + ADT


When considering patients with mHSPC along a risk continuum, from good risk (metachronous low volume: 8-year median overall survival with ADT alone) to poor risk (synchronous high volume: 3-year median overall survival with ADT alone), patients with synchronous low volume and metachronous high volume (median overall survival: 4.5 years with ADT alone) mHSPC may both be considered as intermediate risk disease. As such, the clinical treatment approach for these two subgroups has seen significant overlap. ARPI + ADT have similarly served as the backbone for treatment of these patients. Patients with metachronous, high volume mHSPC have historically accounted for only a small proportion of patients in the published phase III trials, and as such, post-hoc analyses have been underpowered for evaluating this subgroup. Results from the ARCHES trial have demonstrated a 23% decreased hazard of overall mortality in this subgroup with addition of enzalutamide to ADT (HR: 0.77, 95% CI: 0.39 to 1.50).5  Similar results were found in the ENZAMET trial (HR: 0.73, 95% CI: 0.37 to 1.44).

Docetaxel + ADT

Results from the STOPCAP M1 collaborative meta-analysis of individual patient data from GETUG-15, STAMPEDE, and CHAARTED demonstrated that docetaxel addition to ADT in patients with metachronous, high volume prostate cancer is associated with significant improvements in overall survival (HR: 0.64, 95% CI: 0.42 to 0.99),21  which was consistent on follow-up analyses.22 

 Given the relatively increased toxicity with taxanes, along with a subset of patients being “chemotherapy unfit”, it appears that doublet therapy with an ARPI + ADT is the favored treatment approach in patients with metachronous high volume disease, with docetaxel reserved for select patients with higher volume of disease.

Metachronous Low Volume mHSPC

Docetaxel + ARPI + ADT

Similar to metachronous high volume patients, the subgroup analyses of triplet therapy trials assessing metachronous low volume mHSPC patients remain limited. In ARASENS, metachronous low volume disease patients (n = 51) had too few overall mortality events to provide adequate samples size for powered analyses. For the ENZAMET trial, the HR for metachronous low volume patients was 0.64 (95% CI: 0.18 to 2.28).

Figure 15: Overall survival of enzalutamide + ADT + docetaxel vs ADT + docetaxel + non-steroidal anti-androgen for metachronous low volume disease patients in ENZAMET
figure-15-mHSPC-current-state.jpg
ARPI + ADT

Subgroup analyses have consistently demonstrated an overall survival benefit to ARPI addition in patients with low volume mHSPC. Results from the ARCHES trial demonstrated a 37% improved hazard of overall survival with enzalutamide addition to ADT in patients with metachronous low volume mHSPC (HR: 0.63, 95% CI: 0.26 to 1.54). From the ENZAMET trial, patients with metachronous low volume disease had a clinical and statistically significant benefit (HR of 0.47, 95% CI: 0.28 to 0.79).

Docetaxel + ADT

Importantly, there is consistent evidence against the use of docetaxel in this mHSPC subgroup. Results from the CHAARTED trial demonstrated a minimal overall survival in this subgroup (HR: 0.77, 95% CI: 0.51 to 1.18). Furthermore, results from the STOPCAP meta-analysis using CHAARTED and GETUG-AFU15 data demonstrated no overall survival benefit to docetaxel addition (HR: 1.07, 95% CI: 0.75 to 1.54).

Table 1: A summary of overall survival by volume and timing of metastases from the key registration
table-1-mHSPC-current-state.jpg

Conclusions

Although there appears to be increasing utilization of treatment intensification in the real-world setting, less than half of mHSPC patients receive guideline concordant care. While there may be altruistic reasons to avoid treatment intensification secondary to concerns for patient financial toxicity or concerns for the tolerability of these agents, the proven survival benefit conferred by this treatment paradigm should make this approach the clear standard of care. Based on the current evidence, it appears that patients with synchronous, high volume mHSPC benefit from early treatment intensification with triplet therapy in the form of both an ARPI and docetaxel, whereas the remaining mHSPC subgroups benefit most from doublet therapy with ARPI addition to ADT. Radiotherapy to the prostate is also associated with improved overall survival in mHSPC patients with synchronous, low-volume disease and should be considered in these cases.

Related Content: New Pathways for Treating Metastatic Castration-Resistant Prostate Cancer (mCRPC)



Published November 2023

Part of an Independent Medical Education Initiative Supported by  LOXO@Lilly

Written by: Zachary Klaassen, MD MSc Georgia Cancer Center Wellstar MCG Health Augusta, Georgia and Rashid Sayyid, MD MSc University of Toronto Toronto, ON
References:
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  2. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. J Clin Oncol. 2021;39(20):2294-2303.
  3. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. N Engl J Med. 2019;381(2):121-131.
  4. Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(4):323-334.
  5. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2019;37(32):2974-2986.
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  8. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
  9. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20(5):686-700.
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  12. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial. PLoS Med. 2022;19(6):e1003998.
  13. Ryan CJ, Ke X, Lafeuille MH, et al. Management of Patients with Metastatic Castration-Sensitive Prostate Cancer in the Real-World Setting in the United States. J Urol. 2021;206(6):1420-1429.
  14. Freedland SJ, Sandin R, Sah J, et al. Treatment patterns and survival in metastatic castration-sensitive prostate cancer in the US Veterans Health Administration. Cancer Med. 2021;10(23):8570-8580.
  15. Wallis CJD, Malone S, Cagiannos I, et al. Real-World Use of Androgen-Deprivation Therapy: Intensification Among Older Canadian Men With de Novo Metastatic Prostate Cancer. JNCI Cancer Spectr. 2021;5(6).
  16. Deek MP, Van der Eecken K, Phillips R, et al. The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer: The Spectrum Theory Revisited. Eur Urol. 2021;80(5):632-640.
  17. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.
  18. Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial design. Lancet. 2022;399(10336):1695-1707.
  19. Hussain M, Tombal B, Saad F, et al. Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial. J Clin Oncol. 2023;41(20):3595-3607.
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Medicare Advantage: the Who, What, Where, Why… and What’s Next?

Over the past several years, Medicare Advantage (MA) insurance has been heavily criticized by health economists for the large degree of overpayments from Medicare, as well as by patients and physicians for restrictive networks, inconsistent coverage, and often high out-of-pocket costs for patients. Although one may think that MA plans fall under the Medicare/Medicaid umbrella based on the name of these plans, the MA program actually consists of private health plans.