ASCO 2020

ASCO 2020: Genitourinary Cancers Highlights – Kidney and Bladder

(UroToday.com) In this presentation, Dr. Choueiri reviewed four abstracts in kidney and bladder cancer.

LBA1 – Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line chemotherapy in advanced urothelial carcinoma: JAVELIN Bladder 100 phase II interim analysis

In this study, the authors demonstrated an overall survival benefit with maintenance avelumab in patients that did not progress (complete response, partial response, or stable disease) on at least four cycles of induction platinum-based chemotherapy for advanced urothelial carcinoma.

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Dr. Choueiri commented that this is the first switch-maintenance immunotherapy after chemotherapy trial to read out as positive for overall survival benefit in solid tumors and is likely to be an immediate practice change for urothelial cancer treatment. One question he raised is whether a shorter duration of immunotherapy would be equally effective as treating with avelumab to progression. Dr. Choueiri also noted that patients whose tumors were negative for PD-L1 expression or had visceral metastases (poor prognosis overall) seemed to derive less benefit than other patients on trial and asked whether these patients should receive treatment intensification.  

Abstract 5000 – Imvigor010: Primary Analysis from a Phase III Randomized Study of Adjuvant Atezolizumab vs Observation in High-Risk Muscle-Invasive Urothelial Carcinoma.

The standard of care for muscle-invasive urothelial carcinoma consists of neoadjuvant cisplatin-based chemotherapy if possible followed by radical cystectomy. The optimal adjuvant management of these patients is not established. Atezolizumab is approved for second-line therapy in metastatic urothelial carcinoma. In this study, the investigators tested the utility of atezolizumab as an adjuvant therapy by randomizing high-risk patients with muscle-invasive bladder cancer after cystectomy to either observation or q3w atezolizumab as adjuvant therapy for up to 16 cycles. The primary endpoint was disease-free survival in the intention-to-treat population, and the secondary endpoint was overall survival.

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This study did not meet its primary endpoint of improved disease-free survival with adjuvant atezolizumab, regardless of PD-L1 expression within the tumor.

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At 21.9 months of median follow-up, the median overall survival in either cohort had not been reached, and there was no significant difference in survival at the data cut-off between observation and atezolizumab.

Dr. Choueiri concluded that adjuvant PD-L1 therapy is not currently advisable in unselected patients with muscle-invasive bladder cancer after cystectomy. However, he notes that it may be possible to identify patients who would benefit from adjuvant therapy by epigenetic profiling or predict patients more likely to respond to atezolizumab using biomarkers similar to those discussed in Abstract 5011 (high PD-L1 expression plus high tumor mutational burden). Given the overall high-risk for cancer-specific mortality in patients with muscle-invasive bladder cancer, it will be important to continue to do adjuvant trials to try and improve patient outcomes.

Abstract 5001 – Pembrolizumab Plus Axitinib Versus Sunitinib as First-Line Therapy for Advanced Renal Cell Carcinoma: Updated Analysis of KEYNOTE-426

In this abstract, the authors provide 23-month progression-free and overall survival updates for patients with advanced renal cell carcinoma treated on KEYNOTE-426 with pembrolizumab and axitinib as compared to sunitinib. The initial interim analysis data published in 2019 showed improved survival and progression-free survival with combination immunotherapy and TKI therapy relative to TKI therapy with sunitinib. The trial schema is shown here:

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Updated outcome data were summarized as below:

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At extended follow-up, there were no new safety concerns. The relationship between pembro + axi treatment and overall survival was significant in the IMDC intermediate/poor risk groups, and numerically better in the IMDC good risk treatment group. The authors also pursued a 6-month landmark analysis to explore the relationship between the depth of response and survival. These analyses suggested that greater depth of tumor shrinkage was associated with overall survival in the pembro + axi arm.

Dr. Choueiri then put this trial in context with results from the Checkmate-214 trial of nivo/ipi, which showed an overall survival benefit in the intention-to-treat population, but non-statistically significant association with treatment and survival for the IMDC favorable risk group.

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He ended with describing future directions for treatment in advanced renal cell carcinoma, showing the following slides:

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Overall, these trials are generally moving away from sunitinib as the control arm, and are investigating either triplet therapies, the addition of cabozantinib to therapeutic combinations,  or novel therapeutic agents such as the HIF inhibitor MK6482.

Abstract 5006 – Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260). 

Combination nivolumab and ipilimumab is approved for treatment naïve IMDC intermediate and poor-risk clear cell renal cell cancer (ccRCC) based on the Checkmate-214 study, and nivolumab monotherapy is approved for post-tyrosine kinase inhibitor treatment of ccRCC, This study aimed to dissect the response rate to nivolumab monotherapy in treatment naïve ccRCC,  and identify the salvage response rate for nivolumab monotherapy with combination nivolumab and ipilimumab.

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The data are summarized above, with a 32% overall response rate with nivolumab monotherapy in treatment naïve ccRCC, and an overall response rate of 13% with salvage nivolumab and ipilimumab. No complete responses were identified.

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Dr. Choueiri then showed the above slide, overall comparing the overall response rates of sequential and combination therapy for nivolumab and ipilimumab. The ORRs are quite low compared to the combination therapy in untreated ccRCC from Checkmate-214. He concluded that the strategy of single-agent nivolumab followed by ipilimumab salvage cannot be recommended at this time, especially since many patients are unable to receive salvage immunotherapy.

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Finally, he highlighted the Checkmate 209-8Y8 trial looking at nivolumab maintenance in intermediate to poor-risk metastatic ccRCC, which may help further delineate the role of nivolumab monotherapy in this disease.

Presented by: Toni K. Choueiri, MD, Director of the Lank Center for Genitourinary Oncology and Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA

Written by: Alok Tewari, MD, Ph.D., Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 American Society of Clinical Oncology virtual annual meeting (#ASCO20), May 29th-May 31st, 2020 at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020. 

Related Content:

Read: ASCO 2020: JAVELIN Bladder 100 Phase III Results: Maintenance Avelumab + Best Supportive Case vs BSC Alone After Platinum-Based First-Line Chemotherapy in Advanced Urothelial Carcinoma
Read: ASCO 2020: IMvigor010: Primary Analysis from a Phase III Randomized Study of Adjuvant Atezolizumab versus Observation in High-Risk Muscle-Invasive Urothelial Carcinoma
View: KEYNOTE-426: Pembrolizumab plus Axitinib versus Sunitinib as First-Line Therapy for Advanced Renal Cell Carcinoma (RCC) - Brian Rini

ASCO 2020: A Phase II Study of M6620 in Combination with Carboplatin Compared with Docetaxel in Combination with Carboplatin in Metastatic Castration-Resistant Prostate Cancer

(UroToday.com) In this study, Atish Choudhury and colleagues present the rationale and design for a phase 2 study of M6620, an inhibitor of the ATR kinase, in combination with carboplatin for patients with metastatic castration-resistant prostate cancer (mCRPC).

ASCO 2020: Evaluation of a Mainstream Model of Genetic Testing for Men with Prostate Cancer

(UroToday.com) Prostate cancer is the most common non-cutaneous cancer diagnosed in men. All men with metastatic prostate cancer, as well as selected other patients with specific family histories, are recommended to undergo germline genetic testing. Given global limitations on genetic counseling services, this study designed an intervention to have medical oncologists perform pre-genetic testing counseling, arrange genetic testing, and provide initial results. The primary outcome of the intervention was clinician and patient satisfaction, with secondary outcomes of resource allocation and patient uptake of genetic counseling.

ASCO 2020: Genitourinary Cancers Highlights – Prostate, Testicular, and Penile Cancers

(UroToday.com) In this presentation, David R. Wise, MD, PhD, reviewed three presentations in prostate cancer from this conference.

Abstract 5500 – TheraP: A randomized phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel: Initial results (ANZUP protocol 1603)

Prostate cancers express the PSMA molecule on their surface, which has been exploited for targeted therapy. Prior clinical data has shown that the 177Lu-PSMA-617 molecule (LuPSMA), which delivers beta radiation to target cells causing cell death, has encouraging clinical activity from non-randomized studies in mCRPC. Specifically, a phase II study showed 64% of men experienced a 50% reduction in PSA on treatment, with relatively low toxicity. This abstract presented the first randomized study of LuPSMA relative to the standard of care option cabazitaxel in mCRPC. The primary endpoint was the rate of patients experiencing a decrease in PSA by 50%. Secondary endpoints were PSA progression-free survival and adverse events.

The study design is shown below. In total 98 patients were treated with LuPSMA and 85 patients were treated with cabazitaxel.

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The study met its primary endpoint of demonstrating improved rates of 50% reduction in PSA relative to cabazitaxel. There was a 29% absolute improvement in this rate, and a 23% improvement after planned sensitivity analysis given patient dropout.

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PSA progression-free survival data have not met criteria to reject the null hypothesis as of this presentation. The most common side-effects from LuPSMA therapy were thrombocytopenia, dry eyes and dry mouth. The most common Grade 3 or 4 toxicity was thrombocytopenia.

Dr. Wise suggested that this is a promising therapeutic modality that requires additional data including the quality of life, radiographic progression-free survival and overall survival results from this study, as well as results of the phase III VISION trial comparing LuPSMA to standard of care.

Abstract 5501 – Impact of PSMA-targeted imaging with 18F-DCFPyL-PET/CT on clinical management of patients (pts) with biochemically recurrent (BCR) prostate cancer (PCa): Results from a phase III, prospective, multicenter study (CONDOR)

18F-DCFPyL is a PSMA-targeting PET radiopharmaceutical under development for prostate cancer imaging. It is a lysine-linked, urea-based small molecule that is specific for prostate cancer cells. The agent is administered as a bolus injection, then PET imaging is performed 1-2 hours after administration.

In this abstract, the authors presented data from the CONDOR trial, a prospective study designed with the FDA to demonstrate the diagnostic performance of this imaging modality in the context of rising PSA after definitive therapy for localized disease where other imaging modalities fail to identify sites of disease recurrence. The primary endpoint is defined as lower 95% confidence interval of the correct localization rate > 20%. The correct localization rate (CLR) is essentially the positive predictive value for identifying a recurrence site. Imaging findings were compared to a composite standard of truth based on either evaluable histopathology, conventional imaging or confirmed PSA response after radiotherapy targeting the presumed site of recurrence. The secondary endpoint was the rate of change in treatment plans based on this imaging modality.

Importantly for this study, the median PSA value was 0.8 (range 0.17-98.45). 68.8% of patients had PSA < 2.0 ng/mL, and 14.9% of patients had PSA >= 5.0.

With regards to the primary endpoint, the study met its goal with all three independent radiology evaluators have a composite localization rate of >85%

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64% of evaluated subjects had a change in therapeutic management after 18F-DCFPyL scan. Only 3 patients had an adverse safety event, with 1 out of 208 patients experiencing a hypersensitivity reaction.

Dr. Wise concluded that based on this data, (1) 18F-DFCPyL is more sensitive for detection of recurrent prostate cancer than current standard imaging agents, (2) it has a positive predictive value approaching 85% or greater, and (3) with further positive investigation of this agent, this imaging modality may be a highly accurate diagnostic agent for biochemically recurrent prostate cancer.

Abstract 5602 – HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer

Data suggest that cardiovascular mortality is the leading cause of death in patients who have been diagnosed with prostate cancer. This has been attributed in part to cardiovascular side effects from androgen deprivation therapy (ADT). There are two major mechanisms of ADT, designed to decrease serum testosterone to < 50 ng/dL and starve prostate cancer cells of the fuel necessary for growth. LHRH receptor agonists (leuprolide) provide constitutive stimulation and subsequent downregulation of GnRH receptors in the anterior pituitary gland. GnRH receptor antagonists directly block the function of these receptors in the pituitary. LHRH agonists are associated with a flare increase in FSH/LH production and subsequent testosterone levels such that they can cause a clinical flare. This necessitates the concomitant administration of androgen-receptor antagonists with therapy. GnRH antagonists do not have a flare phenomenon and may have an improved cardiovascular safety profile, but must be administered more frequently.

Regulolix is an oral GnRH antagonist administered daily. In this trial, the authors compared regulolix versus a three-month depot injection of the LHRH agonist leuprolide acetate in men with advanced prostate cancer. The primary endpoint of this study was to compare the number of patients with sustained castrate levels of testosterone after 48 weeks of therapy. The study design is shown below.

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This study met its primary endpoint of non-inferiority of regulolix compared to leuprolide for sustained castration. 

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Importantly, patients who came off treatment with either agent had a quicker recovery of testosterone levels if treated with regulolix.

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Finally, in an analysis of cardiovascular events, overall rates were higher in the leuprolide group relative to the regulolix group, especially in patients with a prior history of non-fatal myocardial infarction or non-fatal stroke.

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Dr. Wise concluded that regulolix is an effective mechanism of inducing testosterone suppression and may be beneficial for patients who have a significant history of cardiovascular disease. He intends to use this drug for patients without GI absorption issues and with significant cardiovascular disease history. This will likely require more frequent testosterone checks as the medication is taken orally daily, increasing the risk of medication noncompliance.

Presented by: David R. Wise, MD, PhD, Assistant Professor of Medicine and Urology, Perlmutter Cancer Center and NYU Langone Health, New York, New York

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020. 

ASCO 2020: Short-Term Adjuvant Versus Neoadjuvant Hormone Therapy in Localized Prostate Cancer: A Pooled Individual Patient Analysis of Two Phase III Trials

(UroToday.com) Intermediate and high-risk localized prostate cancers can be treated with surgery or the combination of radiotherapy and hormonal therapy. The optimal timing of hormonal therapy in relation to radiotherapy for localized prostate cancer is an area of active study. In this poster, Daniel E Spratt, MD, and colleagues pool data from prostate-only radiation in the RTOG9413 trial and data from a phase 3 trial of neoadjuvant versus adjuvant hormonal therapy relative to radiation therapy to further explore the optimal timing of hormonal therapy with prostate-only radiotherapy.

In RTOG9413, patients who received prostate-only radiation were randomized to either androgen-deprivation therapy (ADT) for two months prior (neoadjuvant) to the start of radiation therapy, or ADT starting after radiation (adjuvant) and continuing for four months. Patients on this trial who received prostate-only radiation and adjuvant hormonal therapy had numerically higher progression-free survival than patients getting neoadjuvant hormonal therapy. In the other phase 3 trial published by Malone et al of patients undergoing prostate-only radiotherapy, patients were randomized to ADT starting 4 months before radiation (neoadjuvant), or ADT starting with radiation therapy and continuing for 6 months after (adjuvant). The Malone study did not detect any difference in biochemical recurrence rates, overall survival, or late toxicities between either group.

In their pooled analysis, patients from both trials and either neoadjuvant or adjuvant hormonal therapy were combined. This combination gave a cohort of 531 neoadjuvant treated patients, and 534 adjuvantly treated patients. Baseline characteristics were well-balanced between arms. The authors examined the relationship between hormonal therapy timing and various parameters including biochemical failure, progression-free survival, distant metastasis, overall survival and prostate cancer-specific mortality.

The results from this poster show statistically superior rates of biochemical failure (15yr: 33% vs 43%, HR: 1.37 (95%CI: 1.12-1.68), p=0.002), distant metastasis  (15yr: 12% vs 18%, HR: 1.40 (95%CI: 1.00-1.95), p=0.04),  and progression-free survival (15yr: 36% vs 29%, HR: 1.25 (95%CI: 1.07-1.47), p=0.01) with adjuvant hormonal therapy. While numerically better, there was no statistically significant difference in prostate cancer-specific mortality between the arms (15yr: 15% vs 20%, HR: 1.29 (95%CI: 0.95-1.75), p=0.10). There was also no difference in late toxicities between either method.

From this posthoc analysis, the authors suggest that adjuvant hormonal therapy may be preferable to neoadjuvant hormonal therapy when given with prostate-only radiation for the management of localized cancer.

Presented by: Daniel E Spratt, MD, Associate Professor and Chair of Genitourinary Clinical Research, Rogel Cancer Center, University of Michigan, Ann Arbor, MI

Written by: Alok Tewari, MD, PhD, Medical Oncology Fellow at the Dana-Farber Cancer Institute, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020. 

ASCO 2020: Checkpoint Inhibition in Metastatic Urothelial Carcinoma: Timing is Everything

(UroToday.com) In this presentation, Elizabeth Plimack, MD, discussed the findings from LBA1, a phase 3 randomized study of maintenance avelumab in advanced urothelial cancer patients who have not progressed with first-line platinum-based chemotherapy.

ASCO 2020: PDIGREE: An Adaptive Phase III Trial of PD-Inhibitor Nivolumab and Ipilimumab with VEGF TKI Cabozantinib in Metastatic Untreated Renal Cell Cancer (Alliance A031704)

(UroToday.com) Immunotherapy has always been an important part of the treatment paradigm for select patients with metastatic renal cell carcinoma (mRCC). High dose IL-2 was the only FDA approved immunotherapy option from 1992 until nivolumab became approved in 2015 for the second-line treatment of mRCC. Over the past five years, checkpoint inhibitors have moved to the frontline with combination IO/IO therapies (IPI+NIVO [2018]) as well as VEGF/IO combinations (pembrolizumab/axitinib [2019] and avelumab/axitinib [2019]). The benefits of immune checkpoint inhibitors include a generally well-tolerated side effect profile and the possibility of durable response. Many questions remain regarding the optimal duration of treatment, whether or not we can rescue patients without a response with VEGF therapies, and whether or not an adaptive therapy may improve overall survival. This unique study evaluates these questions, with the study schema shown below.

ASCO 2020: CYCLONE 2: A Phase II, Randomized, Placebo-Controlled Study of Abiraterone Acetate plus Prednisone with or Without Abemaciclib in Patients with Metastatic Castration-Resistant Prostate Cancer

(UroToday.com) The cyclin-dependent kinase proteins CDK4 and CDK6 modulate cell cycle progression by phosphorylating and thus inactivating the RB protein. Inhibition of these proteins in breast cancer with multiple agents including abemaciclib is approved both in combination with endocrine therapy or as monotherapy in advanced hormone-receptor-positive disease. As discussed in Abstract 5573, prior phase 2 studies of CDK4/6 inhibition with older androgen receptor antagonists showed no difference in responses, but this may be different within combination with new-antiandrogen therapies. 

ASCO 2020: Quality of Life for the Treatment Sequence of Abiraterone Acetate plus Prednisone Followed by Enzalutamide Versus the Opposite Sequence for Metastatic Castration-Resistant Prostate Cancer: Results from a Phase II Randomized Clinical Trial

(UroToday.com) In a recent publication, Dr. Daniel Khalaf and colleagues reported the results of a randomized, open-label, Phase II crossover trial (NCT02125357) testing the optimal sequence of abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). This study suggested that treating first with abiraterone, then enzalutamide led to a longer time to second prostate-specific antigen (PSA) progression and higher rates of PSA response than treating first with enzalutamide then abiraterone. In a second publication, Dr. Khalaf and colleagues reported that sequencing abiraterone first in was associated with better patient-reported QOL metrics for patients older than 75 years of age as assessed by the FACT-P and PHQ-9 instruments. In this poster, the authors report on the time to quality of life deterioration (TTQOLD) and further examine depression scores and cognitive impairment scores for either sequence of anti-androgen therapies. 

ASCO 2020: Association Between BRCA2 Status and Histologic Variants Intraductal and Cribriform Histology in Prostate Cancer

(UroToday.com) Intraductal (IDC) and cribriform (CRIB) variant histologies in primary prostate cancer are often under-reported but are independent prognostic factors for poor outcomes. Intraductal histology has been associated with germline BRCA2 (gBRCA2) mutation as well as other DNA-damage repair gene alterations in small case series, which suggests that patients with this histology at prostatectomy or on biopsy should undergo germline genetic testing.

ASCO 2020: Clinical Outcomes and Markers of Treatment Response in a Randomized Phase II Study of Androgen Deprivation Therapy with or Without Palbociclib in RB-Intact Metastatic Hormone-Sensitive Prostate Cancer

(UroToday.com) Inhibition of the cell cycle enzymes CDK4 and CDK6 are standard of care interventions in both adjuvant management of breast cancer as well as in the metastatic setting. Preclinical models of prostate cancer also suggest the importance of CDK4/6 function in the context of androgen signaling and expression of retinoblastoma (RB). In this poster, Dr. Phillip Palmbos and colleagues report results and molecular correlatives from a Phase II randomized study (NCT02059213) in patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT) and antagonism of the androgen receptor (AR) with bicalutamide +/- the CDK4/6 inhibitor palbociclib. Inclusion criteria are below, and importantly, required intact expression of RB. The primary endpoint of the study was to compare the rate of prostate-specific antigen (PSA) decrease to < 4 ng/mL after 28 weeks of therapy. Secondary endpoints were safety, rate of achieving PSA < 0.2 ng/mL, and response rates such as biochemical progression-free survival and radiologic response rates. Correlative endpoints were the number of circulating tumor cells (CTCs) at baseline and on therapy as well as transcriptome and mutational assessment of tumor tissue.

ASCO 2020: JAVELIN Bladder 100 Phase III Results: Maintenance Avelumab + Best Supportive Care vs BSC Alone After Platinum-Based First-Line Chemotherapy in Advanced Urothelial Carcinoma

(UroToday.com) Advanced urothelial carcinoma resulted in over 200,000 deaths across the world in 2018. Though the majority of patients eligible for such therapy respond to platinum-based chemotherapy, disease progression occurs relatively quickly and a half or less of patients receive second-line treatment. Though PD-L1/PD-1 immune checkpoint blockade (ICB) agents are standard 2nd-line therapy for disease progression after platinum, not all patients receive this therapy and only a minority of patients have a durable clinical benefit. Avelumab, an antibody against PD-L1, is approved in the second-line post-platinum treatment setting.

ASCO 2020: Discussant: Promising Therapeutic Targets in Prostate Cancer

(UroToday.com) Following three Poster Discussion presentations assessing novel treatment approaches in advanced prostate cancer, “TRANSFORMER: Bipolar androgen therapy (BAT) versus enzalutamide (E) for castration-resistant metastatic prostate cancer (mCRPC)”, “A phase I, open-label, multicenter study to assess the safety, pharmacokinetics, and preliminary antitumor activity of AZD4635 both as monotherapy and in combination in patients with advanced solid malignancies: Results from prostate cancer patients (NCT02740985)”, and “ProCAID: A randomized double-blind phase II clinical trial of capivasertib (C) in combination with docetaxel and prednisolone chemotherapy (DP) in metastatic castration-resistant prostate cancer (mCRPC)”, Ana Aparicio, MD, provided her perspective on these emerging promising therapeutic targets in prostate cancer. However, before discussing her thoughts, here is a summary of the abstracts upon which this discussion is based.

ASCO 2020: A 13-Years Follow-up Analysis of a Phase III Trial Cohort: Late Toxicities and Recurrences in Patients with Clinical Stage I Nonseminomatous Germ Cell Tumor After One Cycle of Adjuvant BEP Versus Primary Retroperitoneal Lymph Node Dissection

(UroToday.com) A randomized Phase III trial published in 20081 demonstrated that one cycle of bleomycin, etoposide, and platinum (BEP) therapy was associated with a lower risk of tumor recurrence relative to retroperitoneal lymph node dissection for an unselected population of clinical-stage 1 nonseminomatous germ cell tumors. To examine long term toxicities and confirm long term outcomes for these patients, Andreas Hiester, MD, and colleagues presented 12-year follow-up data of the patients initially enrolled in this clinical trial.

ASCO 2020: Overall Survival Results of Phase III ARAMIS Study of Darolutamide Added to Androgen Deprivation Therapy for Non-metastatic Castration-Resistant Prostate Cancer

(UroToday.com) There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients. These agents, as well as darolutamide, were subsequently approved on the basis of demonstrated improvements in metastasis-free survival. While metastasis-free survival has been shown to be a reasonable surrogate for overall survival in this population, there were questions as to whether the benefit of using androgen-axis inhibitors would translate to overall survival benefits, in part due to the differential survival effect seen according to disease burden in CHAARTED. While overall survival data from SPARTAN have been previously reported, Karim Fizazi, MD, PhD, and colleagues present the overall survival data assessing darolutamide in non-metastatic castration-resistant prostate cancer from ARAMIS in the Poster Discussion section of the 2020 American Society of Clinical Oncology Virtual Annual Meeting.

As a brief reminder, darolutamide is an androgen receptor inhibitor with a structure distinct from apalutamide and enzalutamide. Perhaps as a result of this structural difference, indirect comparisons from network meta-analysis have shown it to have a favorable safety profile compared to these other agents.

ASCO 2020: DUTRENEO Trial: A Randomized Phase II Trial of DUrvalumab and TREmelimumab Versus Chemotherapy as a NEOadjuvant Approach to Muscle-Invasive Urothelial Bladder Cancer Patients Prospectively Selected by an Interferon-Gamma Immune Signature

(UroToday.com) Cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer (MIBC) can result in pathological complete responses and confers an overall survival benefit for patients undergoing this treatment. However, many patients do not receive neoadjuvant platinum chemotherapy due to medical comorbidities or other factors. There is a suggestion that neoadjuvant immune checkpoint blockade (ICB) can induce pathological complete response in MIBC patients, perhaps more frequently in patients with tumors over-expressing PD-L1 or expressing genes related to inflammation.

ASCO 2020: Cost-Effectiveness of Novel Antiandrogens for Treatment of Nonmetastatic Castrate-Resistant Prostate Cancer

(UroToday.com) The landscape of treatment options for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) has changed rapidly since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients. These agents, as well as darolutamide, were subsequently approved based on demonstrated improvements in metastasis-free survival. Since this time, further data have been presented demonstrating an overall survival benefit to these agents.

ASCO 2020: Discussant: Advanced Prostate Cancer: Putting Survival Into Perspective

(UroToday.com) There has been a rapid evolution in treatment options for patients with non-metastatic castration-resistant prostate cancer since the spring of 2018. Up until the presentation of SPARTAN and PROSPER trials, reporting on the use of apalutamide and enzalutamide in non-metastatic castration-resistant prostate cancer, at GU ASCO in February 2018, there were no specifically approved treatment options for these patients. These agents, as well as darolutamide, were subsequently approved based on demonstrated improvements in metastasis-free survival. While metastasis-free survival is a reasonable surrogate for overall survival in this population, there were questions as to whether the benefit of using androgen-axis inhibitors would translate to overall survival benefits, in part due to the differential survival effect seen according to disease burden in CHAARTED.

ASCO 2020: Prostate Cancer Biomarker Enrichment and Treatment Selection (PC-BETS) Study: A Canadian Cancer Trials Group Phase 2 Umbrella Trial for MCRPC (IND223/IND224)

(UroToday.com) Genomic characterization of metastatic castrate-resistant prostate cancer has identified commonly occurring alterations but also recurrently altered genes at much lower frequencies. In this presented poster, the authors aimed to evaluate the anti-tumor activity of novel targeted therapies in patients with metastatic castrate-resistant prostate cancer. For the purpose of this goal, the authors initiated an umbrella trial using circulating tumor DNA (ctDNA) to enrich accrual for cancers with alterations that may predict the response (NCT02905318, NCT03385655).

ASCO 2020: Late Toxicities and Recurrences in Patients with Clinical Stage 1 Nonseminomatous Germ Cell Tumor After 1 Cycle of Adjuvant BEP vs. Primary Retroperitoneal Lymph Node Dissection – a 13 Years Follow-up Analysis of a Phase 3 Trial Cohort

(UroToday.com) One cycle of adjuvant BEP chemotherapy has shown superiority and a clear benefit in recurrence-free survival over retroperitoneal lymph node dissection (RPLND) in patients with clinical stage 1 non-seminoma germ cell tumors, according to a German randomized phase 3 trial published in the Journal of Clinical oncology back in 2008.1

In this poster, the authors present updated results of this trial, including recurrences and patient-reported late toxicities after 13 years of follow-up.

The study design is shown in Table 1. Patients in arm A received 1 cycle of BEP chemotherapy, and patients in arm B underwent RPLND surgery.

Table 1- Study design:

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All patients answered specific questionnaires about general and specific chemotherapy- and surgery-related items, with all questions being closed-ended questions (multiple choice). The results demonstrated a benefit in progression-free survival in patients treated with BEP chemotherapy but no difference in the overall survival, as can be seen in Figure 1.  Table 2 demonstrates the number of additional recurrences that occurred in this extended follow-up period. Overall, there was only one more single recurrence in each arm during this extended follow-up time. In the original study, there were 15 recurrences in the RPLND arm and only two recurrences in the BEP chemotherapy arm.

Figure 1 – Progression-free and overall survival:

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Table 2 – Follow-up and oncological findings:

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When assessing patient-reported toxicities, the only significant difference was seen with retrograde ejaculation being more common in the RPLND arm with 24% versus 9%, p=0.01 (Table 3).

Table 3 – Patient-reported toxicities:

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The study’s limitations include lack of CTC grading of toxicities, a limited number of patients that were accrued, and the fact that this study was based on patient-reported outcomes with no objective medical data available.

The authors concluded that after 13 years of follow-up, recurrences in clinical-stage one non-seminoma germ cell tumor remains to be significantly more frequent with retroperitoneal lymph node dissection than with BEP chemotherapy. There was no excess mortality due to secondary malignancies in this extended follow-up, and late toxicities were not different between one cycle of BEP and RPLND.

Presented by: Andreas Hiester, Department of Urology, Heinrich-Heine-University, Düsseldorf, Germany

Written by: Hanan Goldberg, MD, MSc., Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, Twitter: @GoldbergHanan, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020. 

References:

  1. Albers P, Siener R, Krege S, et al. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2008; 26(18): 2966-72.
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