IntroductionThere 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.
Despite these regulatory approvals, supplemented by international guidelines recommendations in favor of their use in appropriate clinical settings, the utilization of these agents commonly lags in clinical practice leading to guideline-discordant care. Additionally, the increased utilization of these agents in earlier disease stages, particularly the metastatic hormone-sensitive setting, has important downstream effects for secondary treatment selection in the castrate-resistant setting.
In this Center of Excellence article, we will discuss the current state of treatment utilization for mCRPC patients in North America and provide a contemporary approach to the management of mCRPC patients who may have received treatment intensification in the metastatic hormone-sensitive setting.
Real-World Treatment Utilization Patterns in North AmericaMedicare
In 2023, Freedland et al. published the results of a population-based analysis of Medicare fee-for-service claims of mCRPC patients with continuous insurance coverage ≥1 year before and ≥6 months after diagnosis (unless patients died) between January 2014 and June 2019.1 It is worth noting that only docetaxel and the androgen receptor pathway inhibitors (APRIs) abiraterone acetate and enzalutamide were approved in the mCRPC space by January 2014, with poly ADP ribose polymerase (PARP) inhibitors and LuPSMA not approved until 2020 and 2022, respectively.2-6
This analysis included 14,780 mCRPC patients, with a median age of 76 years and a median follow-up (from mCRPC diagnosis) of 17 months. Significantly, 22% of men did not receive any documented life-prolonging therapy following progression to mCRPC. In the overall cohort, 78% received ≥1, 42% received ≥2, and 20% received ≥3 lines of therapy in the mCRPC setting. The median time from the start of first line of mCRPC therapy to the next agent was 14 months, with decreasing subsequent intervals from second line to the third line agent (11 months) and third line to fourth line agent (9 months). The most common fist to second line treatment sequences among men with ≥2 lines were:
- ARPI followed by an alternative ARPI (33%)
- Chemotherapy followed by an ARPI (14%)
- ARPI followed by chemotherapy (13%)
Among those receiving an ARPI in the 1st line mCRPC treatment setting, only 28% received additional therapy with a different drug class. The median survival after progression to mCRPC was 25.6 months.
Published in 2023, Swami et al. used the SEER-Medicare claims database to identify mCRPC patients 65 years of age or older between 2007 and 2019. In contrast to the prior study by Freedland et al., the index date in this trial was defined as the start of first line therapy (mCRPC diagnosis in the prior study). This analysis included 4,758 patients. Among these patients who already received a first line treatment, 57% received second line treatment, with almost 50% of these patients progressing to third line therapy.
The most commonly used agents in the first, second, and third line treatment settings, respectively, were:
- Abiraterone acetate + prednisone (42%, 33%, and 18% in the 1st, 2nd, and 3rd line)
- Enzalutamide (22%. 33%, and 25%, respectively)
- Docetaxel (22%, 14%, and 22%, respectively)
On average, patients had 1.2 inpatient admissions, 1.1 emergency room visits, and 27.6 outpatient visits per year during follow-up. The median overall survival from the initiation of first line mCRPC treatment was 21.5 months.7
Ontario Provincial Data
In 2022, Shayegan et al. published the results of a longitudinal, population-based analysis utilizing province-wide, Ontario-based administrative claims data of mCRPC patients. All included patients (n=944) received first line mCRPC treatment between January 2016 and April 2020. The most commonly used first line therapies were:
- Abiraterone acetate + prednisone (52% of cohort)
- Enzalutamide (41%)
- Docetaxel (4%)
- Radium-223 (3%)
- Docetaxel (39% of 2nd line therapies following an ARPI)
- Radium-223 (28%)
- Alternative ARPI (20%)
Contemporary mCRPC Management: Sequencing Available DrugsAs first line treatment regimens for mCRPC have evolved since 2015, so has our cohort of patients with mCRPC. As such, we can distinguish between two cohorts of mCRPC patients:
- Historical mCRPC: Patients progressing on ADT alone
- Intensified mCRPC: Patients progressing on ADT + an ARP|I or docetaxel
Currently approved 1st line treatment regimens for mCRPC patients include:
- Abiraterone acetate + prednisone
- Olaparib + abiraterone acetate + prednisone in BRCA1/2-mutated patients
- Talazoparib + enzalutamide in homologous recombination repair-mutated patients
Prior ADT + ARPI
The majority of patients progressing to mCRPC following prior treatment with an ARPI +ADT will likely receive docetaxel, given the long-term evidence for its efficacy and safety in this setting.9 However, prospective randomized evidence for this approach (ARPI docetaxel) is limited. Treatment with an alternative ARPI in this setting is also associated with limited clinical benefit.10
One option in this setting may be a PARP inhibitor, olaparib. PROfound was a randomized, open-label, phase III trial evaluating efficacy and safety of olaparib versus enzalutamide or abiraterone in patients with mCRPC with alterations in any of 15 predefined genes with a direct or indirect role in homologous recombination repair whose disease had progressed on prior new hormonal agent therapy.11 Cohort A included patients with alterations in BRCA1, BRCA2 or ATM, while Cohort B patients included any one of 12 other homologous recombination repair alterations (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L). Patients were randomized 2:1 to olaparib (300 mg BID) or the physician’s choice of enzalutamide (160 mg/day) or abiraterone (1000 mg/day + prednisone 5 mg BID). The primary endpoint was radiographic progression-free survival (rPFS) in Cohort A, assessed by blinded independent central review and analyzed via a stratified log-rank test. Crossover to olaparib was allowed after blinded independent central review progression.
Among patients in Cohort A (BRCA1/2, ATM), imaging-based progression-free survival was significantly improved with the use of olaparib (median PFS: 7.4 versus 3.6 months, HR: 0.34, p<0.001).
Overall survival benefits were observed in the BRCA1/2 and ATM altered cohort with median overall survival improved from 14.7 to 19.1 months (HR: 0.69, 95% CI: 0.50 – 0.97, p=0.02). Significantly, no overall survival benefit was observed in cohort B (HR: 0.96, 95% CI: 063 – 1.49).
Accordingly, olaparib may be an option for mCRPC patients who progressed following prior ARPI + ADT, although this option is limited to those patients with alterations in BRCA1/2 or ATM.
In a similar setting, the use of rucaparib (600 mg twice daily) in mCRPC patients with BRCA1/2 or ATM alterations who had disease progression following a prior ARPI demonstrated significant improvements in imaging-based progression-free survival (median:10.2 versus 6.4 months; HR: 0.61, 95% CI: 0.47 to 0.80, p<0.001), compared to a physician’s choice control (docetaxel or an alternative ARPI). This benefit was most pronounced in the BRCA patient subgroup (median: 11.2 versus 6.4 months; HR: 0.50, 95% CI: 0.36 to 0.69, p<0.001).
The PSMAfore study (NCT04689828) was recently presented at ESMO 2023 and evaluated the use of 177Lu-PSMA-617 in taxane-naïve mCRPC patients with disease progression following use of an ARPI. This is a phase III, open-label, multi-center, randomized study comparing 177Lu-PSMA-617 to an ARPI change (abiraterone or enzalutamide). All eligible patients were candidates for an ARPI change following progression on one ARPI and had ≥1 PSMA positive lesion(s) and no exclusionary PSMA negative lesions by 68Ga-PSMA-11 PET/CT. Candidates for PARP inhibition and patients with prior systemic radiotherapy (<6 months ago), immunotherapy (except sipuleucel-T), or chemotherapy (except [neo]adjuvant >12 months ago) were ineligible. Randomization was 1:1 to open-label 177Lu-PSMA-617 (7.4 GBq every 6 weeks for 6 cycles) or an ARPI change (abiraterone or enzalutamide). Importantly, patients randomized to ARPI could crossover to 177Lu-PSMA-617 following centrally reviewed radiographic progression. The trial design for PSMAfore is as follows:
Overall, there were 468 patients randomized. The median patient age was 71 – 72 years and median PSA was 14.9 – 18.4 ng/ml. Notably, 84.2% of patients that had an rPFS event (primary endpoint) in the ARPI change arm subsequently went on to receive crossover 177Lu-PSMA-617. At the primary analysis (median follow-up, 7.3 months; n=467), the primary endpoint of rPFS was met (HR :0.41, 95% CI: 0.29 to 0.56).
Among men with measurable disease, the objective response rate was 51% versus 15% in favor of the 177Lu-PSMA-617 arm (complete response: 21% versus 3%). The median duration of response was 13.6 months for 177Lu-PSMA-617 versus 10.1 months for ARPI change. To date, overall survival data remains immature (45.1% of death events have occurred). In the pre-specified cross-over adjusted analysis, there was a trend towards an overall survival benefit in the 177Lu-PSMA-617 arm (HR: 0.80. 95% CI: 0.48 to 1.33). In the unadjusted, intention to treat analysis, the hazard ratio was 1.16 (95% CI: 0.83 to 1.64).
Based on these results, it appears that 177Lu-PSMA-617 will also emerge as an attractive treatment option in PSMA-PET/CT positive mCRPC patients who progress on prior ARPI therapy.
ADT + Docetaxel
What about patients who received docetaxel + ADT treatment intensification in the castrate-sensitive setting? Abiraterone (COU-AA-301)13 and enzalutamide (AFFIRM)14 have both demonstrated overall survival benefits when used in the post-docetaxel treatment setting. There is additionally evidence for the use of cabazitaxel in this setting, following the results of the TROPIC trial,15 although it is currently recommended that patients ‘see’ an ARPI early on in their disease course.
ADT + Docetaxel + ARPI
The emergence of ‘triplet’ therapy options for the management of metastatic hormone sensitive prostate cancer (mHSPC), particularly those with synchronous, high-volume disease, has been an exciting development in this disease space. While early exposure to a combination of ADT + docetaxel + an ARPI [darolutamide16 (ARASENS) or abiraterone17 (PEACE-1)] is associated with overall survival benefits, it does ‘exhaust’ therapeutic agents early in the disease process, limiting options further downstream.
In addition to the aforementioned PARP inhibitors, olaparib and rucaparib, Lu-PSMA and cabazitaxel are options in this setting. The evidence for Lu-PSMA in this setting comes from the phase III VISION and phase II TheraP trials.16,17
TheraP was an open label, phase II trial of 200 men were randomized to either 177Lu-PSMA-617 or cabazitaxel. To screen into the study, all men had both 68Ga-PSMA-11 and 18F-FDG PET/CT and were required to have high PSMA-expression (at least one site with SUVmax≥20) and no sites of FDG-positive/PSMA-negative disease. All patients had progressive disease with rising PSA ≥20 ng/mL after docetaxel and 91% had received prior enzalutamide or abiraterone. After a median follow up of 13 months, 177Lu-PSMA-617 significantly improved PSA-PFS compared with cabazitaxel (HR: 0.63, 95% CI: 0.46 to 0.86) and a had a much higher PSA50 rate (66% vs 37%). Updated analysis were presented at ASCO 2022 after a median follow-up of 36 months with PFS continued to favor the 177Lu-PSMA-617 arm (HR: 0.62, 95% CI: 0.45 to 0.85). There were no significant differences in restricted mean survival time overall survival between the two arms (19.1 months in 177Lu-PSMA-617 arm versus 19.6 months in cabazitaxel arm, 95% CI for difference: -3.7 - +2.7).
VISION was an international, randomized, open-label phase III study that evaluated 177Lu-PSMA-617 in men with PSMA-positive mCRPC who had previously received treatment with an ARPI and one or two prior lines of taxane chemotherapy. Importantly, patients must have had PSMA-positive disease on the basis of a central review of 68Ga-PSMA-11 staging scans. PSMA positivity was defined as uptake greater in metastatic lesions than in the liver. Further, they could have no PSMA-negative metastatic lesions. Following enrollment, patients were randomized in a 2:1 fashion to receive either 177Lu-PSMA-617 plus standard of care or standard of care alone. Standard of care treatments were at the discretion of the treating investigator; however, cytotoxic chemotherapy, immunotherapy, and radium-223 were explicitly excluded. Most patients received alternative androgen-directed therapies while others received palliative radiotherapy and glucocorticoids.
Over a median study follow-up of 20.9 months, treatment with 177Lu-PSMA-617 + standard of care significantly improved overall survival by a median of 4 months (median: 15.3 vs 11.3 months; HR: 0.62, 95% CI: 0.52 to 0.74; p < 0.001), compared to standard of care alone, in the overall cohort of all randomized patients (n=831):
There is also evidence for cabazitaxel in the post-ARPI and docetaxel setting. Published in 2019, the CARD trial randomized 255 patients who had previously received both docetaxel and an ARPI (either abiraterone or enzalutamide) to either cabazitaxel or the other ARPI. Over a median follow-up of 9.2 months, patients who received cabazitaxel had a significantly lower risk of imaging-based progression or death (median: 8 versus 3.7 months; HR: 0.54, 95% CI: 0.40 to 0.73). Overall survival was similarly improved with the use of cabazitaxel (13.6 months vs 11 months; HR: 0.64, 95% CI: 0.46 to 0.89).18
The schematic below summarizes the current level of evidence for mCRPC agents based on prior receipt of an ARPI and/or docetaxel.
ConclusionsWhile numerous agents have become available for the treatment of mCRPC patients, the reality is that the majority of patients only receive one line of treatment in the real-world setting. In addition to the discovery and development of novel drug targets/combinations in this disease space, improved efforts are needed to understand the discord between clinical trials and ‘real-world’ mCRPC patient populations, particularly with regards to treatment implementation. With the increased utilization of these agents in the castrate-sensitive setting, a nuanced approach to the management of these patients in the more advanced castrate-resistant phase will be needed, accounting for prior treatments received.
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