Advances in Genitourinary Cancers at ASCO22

Guest host Dr. Neeraj Agarwal, of the University of Utah Huntsman Cancer Institute and the ASCO Daily News editor-in-chief, discusses updated results from the ENZAMET trial and other advances in prostate cancer and highlights key studies in kidney and bladder cancer with Dr. Jeanny Aragon-Ching, of the Inova Schar Cancer Institute.   TRANSCRIPT  Dr. Neeraj Agarwal: Hello! My name is Dr. Neeraj Agarwal. I'm the director of the Genitourinary (GU) Cancer Program and a professor of Medicine at the University of Utah Huntsman Cancer Institute and editor-in-chief of ASCO Daily News.  I'm delighted to have Dr. Jeanny Aragon-Ching, who is one of the associate editors at the ASCO Daily News, to discuss key oral abstracts in the genitourinary cancers, which were presented in the recently concluded 2022 ASCO Annual Meeting.  Dr. Aragon-Ching is a medical oncologist and the clinical program director of the Genitourinary Oncology Program at the Inova Schar Cancer Institute in Virginia.   Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at the ASCO.org\podcasts.  Jeanny, it is great to be speaking with you again and to discuss these practice influencing oral abstract sessions.  Dr. Jeanny Aragon-Ching: Thanks, Neeraj. I'm so very happy to be here. So, let's begin with Abstract 5000 and the ANZUP 1603 trial. This is actually the therapy trial lutetium versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC), progressing after docetaxel overall survival after a median follow-up of 3 years. Neeraj, what can you tell us about the study?  Dr. Neeraj Agarwal: Of course, Therapy Study is a randomized trial comparing treatment with lutetium PSMA-617 cabazitaxel in mCRPC patients progressing after docetaxel.  Only patients with high PSMA expression and no sites of fluorodeoxyglucose (FDG) positive, and PSMA negative disease were eligible. Previously, the ANZUP investigators showed a significant improvement in the primary endpoint of the study, which was a prostate-specific antigen (PSA) 50% response rate with 66% for those in the lutetium PSMA arm versus 37% on the cabazitaxel arm. So, PSA 50% response was higher in the lutetium therapy arm over cabazitaxel.  Investigators also reported significant results for key secondary endpoints of progression-free survival with the hazard ratio of 0.63 favoring lutetium therapy, which translates into a 37% reduction in the risk of prostate-specific antigen (PSA), pain or radiographic progression and decreased adverse events of grade 3 or 4 side effects for patients in lutetium PSMA therapy compared to cabazitaxel.  So, this was presented in the past. In this update, Drs. Michael Hoffman and Ian Davis report results on this secondary endpoint of overall survival after a median follow-up of 3 years. In addition to reporting on overall survival, the reanalysis of PSA and radiographic progression-free survival continued to significantly favor the lutetium PSMA arm with a 38% reduction in the risk of progression. After a median follow-up of 36 months, the overall survival was similar in those assigned to lutetium PSMA versus cabazitaxel with a restricted mean survival time of 19.1 months for lutetium therapy versus 19.6 months for cabazitaxel therapy, respectively.  No additional safety signals were identified with the longer follow-up. An important point here is that the therapy trial was never powered for overall survival.  Dr. Jeanny Aragon-Ching: So, this is a very important study indeed, Neeraj. So, what do you think is the key takeaway from this trial?  Dr. Neeraj Agarwal: The key takeaway message here is that while the lutetium PSMA is a suitable option for men with PSMA-positive mCRPC progressing after docetaxel. The similar overall survival compared to cabazitaxel indicates cabazitaxel is also a suitable option for those patients with high PSMA expression.  However, while lutetium PSMA-based therapy and cabazitaxel had similar overall survival results, treatment with lutetium PSMA was associated with fewer adverse events and better patient-reported outcomes. So, given the option of both being available, after disease progression on docetaxel, I would lean towards using lutetium PSMA therapy first, followed by cabazitaxel chemotherapy.  Dr. Jeanny Aragon-Ching: That's wonderful, Neeraj. Now moving on to LBA5004, investigators reported updated overall survival outcomes in the ENZAMET Trial an international cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer. What are your thoughts about this abstract?  Dr. Neeraj Agarwal: So, ENZAMET was a large phase 3 trial in the metastatic hormone-sensitive prostate cancer setting, which randomly assigned 1,125 patients to androgen deprivation therapy or they called it testosterone suppression therapy, which I like more, plus older antiandrogen such as bicalutamide versus testosterone suppression therapy plus enzalutamide.  The trial originally matches the primary endpoint with a 33% improvement in overall survival with enzalutamide. One of the unique aspects of the trial was that patients were allowed to receive docetaxel during the protocol treatment and the receipt of docetaxel had to be predetermined before randomization.  So, a total of 503 patients received docetaxel, which represents 45% of all patients randomly assigned on the ENZAMET trial. In this timely update at the 2022 ASCO Annual Meeting, Drs. Ian Davis and Chris Sweeney report that a combination of enzalutamide plus testosterone suppression therapy continues to improve survival with a 30% reduction in the risk of death with enzalutamide after an additional 3 years of follow-up.  Interestingly, in the subgroup of patients who received concurrent docetaxel, there was no improvement in the overall survival with enzalutamide. Having said that, this is a subgroup analysis for which that trial was not independently powered, and the receipt of docetaxel chemotherapy was determined based on physician and patient judgment or their choice, and it was not randomized. So, I would say that in the overall ENZAMET trial population, the receipt of enzalutamide was associated with improved progression-free survival as well as overall survival.  Dr. Jeanny Aragon-Ching: That's a very great summary, Neeraj. So, what do you think is the key takeaway from this abstract?  Dr. Neeraj Agarwal: The updated results of the ENZAMET trial with a longer median follow-up of almost 6 years, showed that enzalutamide continues to show improved overall survival in men with metastatic hormone-sensitive or castration-sensitive prostate cancer.  Furthermore, the effect of enzalutamide on overall survival is independent of the receipt of docetaxel in the ENZAMET trial. Based on these results, upfront intensification of androgen deprivation therapy with a deeper androgen access inhibitor remains the standard of care and should be offered to all patients with metastatic castration-sensitive prostate cancer.  So, I think we have discussed this really exciting practice influencing prostate cancer abstract, Jeanny. I would like to move on to kidney cancer for a moment. I think we can discuss the CheckMate-9ER, which is Abstract 4501, which reported on the association between depth of response and clinical outcomes.  So, this was an exploratory analysis in patients with previously untreated advanced renal cell carcinoma who were treated with cabozantinib with nivolumab versus sunitinib in the CheckMate-9ER trial. So, any good news from this analysis, Jeanny?  Dr. Jeanny Aragon-Ching: Yeah, so as you may recall, at the 2022 Genitourinary Cancers Symposium, Dr. Powles reported updated results for the randomized phase 3 trial called CheckMate-9ER and this showed that treatment-naive patients with advanced renal cell carcinoma had a significantly improved progression-free survival. The hazard ratio was like 0.56 and overall survival of 0.7 and this is with nivolumab and cabozantinib compared to sunitinib alone.  So, in this exploratory analysis, Drs. Cristina Suárez and Andrea Apolo decided to evaluate the relationship between the depth of response and clinical outcomes. So, depth of response was defined as a breast percent reduction from baseline in the sum of diameters of targeted lesions. And this has been previously reported to be associated with efficacy outcomes in patients with advanced renal cell carcinoma treated with checkpoint inhibitors or targeted agents.  Now for this particular analysis, patients with a partial response were further divided into 3 subgroups. So, it was based on partial response with different tumor reduction thresholds.  So, for instance, patients in the first subgroup of partial responders, they call them PR 1, had a tumor reduction of at least 80%. And then PR 2 responders were categorized as those with a tumor reduction of less than 80%, but at least 60%. The last subgroup which is called PR 3 included patients with less than 60% tumor reduction.  So, all of these other subgroups, which included complete responders, stable disease, and progressive disease remain the same. So, overall, deeper responses were associated with improvements in progression-free survival (PFS) and overall survival (OS) benefits for patients with advanced renal cell carcinoma.  However, the association between the depth of response and improved PFS benefit for patients treated with nivolumab and cabozantinib was noticeably linear compared to those treated with sunitinib.  It's also interesting to note that the median duration of response improved numerically with each incremental depth of response with nivolumab plus cabozantinib arm but not really seen in this sunitinib arm.  Dr. Neeraj Agarwal: Very interesting data. So, what is your key takeaway from this trial, Jeanny?  Dr. Jeanny Aragon-Ching: Yeah, so I think the results from this exploratory analysis are very exciting and provide a useful tool that clinicians can further use to help counsel our patients when reviewing their scans, for instance, in the clinic.  Furthermore, based on such a robust correlation of the depth of response with PFS and OS, it may be time for us to consider objective response as a surrogate for PFS and OS by the regulatory bodies to expedite the hopeful drug approval.  So, moving on, Neeraj, to Abstract 5006. This is assessing the intermediate clinical endpoints as potential surrogates for overall survival in men with metastatic hormone-sensitive prostate cancer. Why do you think this study should be on our radars?  Dr. Neeraj Agarwal: During the last several years we have seen many of the agents, typically given for castrate-resistant prostate cancer, moving up front to the castration-sensitive setting. And this is especially true for androgen receptor access targeting agents like enzalutamide or abiraterone, which have moved from castration-resistant prostate cancer (CRPC) to castration-sensitive prostate cancer (CSPC) setting and chemotherapy with docetaxel.  An exciting outcome from these advances is a significant improvement in the overall survival of our patients, which is now extending beyond 6 to 7 years as reported by many of the recent trials.  However, as a consequence of these improvements, phase 3 clinical trials in the hormone-sensitive metastatic prostate cancer setting are taking significantly longer to report overall survival outcomes, thus requiring identifying valid surrogates in order to expedite results.  So, in Abstract 5006, Drs. Susan Halabi and Chris Swinney investigate the use of radiographic progression-free survival and clinical progression-free survival as intermediate clinical endpoints as potential surrogates for overall survival in men with metastatic hormone-sensitive prostate cancer.  This study was performed through the STOPCAP M1 Collaboration, which is an international collaboration of multiple investigators from institutions across the planet. Individual patient-level data from more than 8,500 patients from the randomized phase 2 and 3 clinical trials in patients with metastatic hormone-sensitive prostate cancer conducted between 1994 and 2013 were analyzed.  The median overall survival was 49.4 months in the cohort, and the radiographic progression-free survival and clinical progression-free survival were 26.8 and 25.2 months respectively.  The surrogate threshold effect was 0.82 for radiographic progression-free survival, and 0.84 for clinical progression-free survival, which tells us that both radiographic PFS and clinical PFS strongly correlate with overall survival. So, I think we have discussed exciting prostate cancer data and bladder cancer data.  Jeanny, I would like to move on to the bladder cancer and would like your take on this abstract, which created lots of buzz about cell-free DNA methylation as a predictive biomarker of response to neoadjuvant chemotherapy for patients with muscle-invasive bladder cancer in the SWOG S1314 trial, which is Abstract 4506. So, Jeanny, why should this study be on our radar?  Dr. Jeanny Aragon-Ching: Yes, absolutely. So, neoadjuvant chemotherapy has been the standard of care in muscle-invasive bladder cancer. However, treatment is often intense, the overall benefit is small, and there are no established biomarkers to identify patients who will benefit the most.  So, in this study, Drs. Yi-Tsung Lu and Amir Goldkorn characterize cell-free DNA methylation patterns from patients receiving neoadjuvant chemotherapy in the SWOG S1314 trial, and they correlated the methylation signatures with pathologic response.  So, the SWOG trial is a randomized phase 2 trial that primarily investigated a predictive biomarker for neoadjuvant chemotherapy in patients with localized muscle-invasive bladder cancer.  Now, in this exploratory analysis, the investigators developed a methylation-based response score, predictive of pathologic response to neoadjuvant chemotherapy for patients with localized muscle-invasive bladder cancer, by testing pre-treatment and on-treatment cycle 2, day 1 plasma cell-free DNA.  So, the results indicated that the combination of the methylation base response score and circulating bladder DNA fraction successfully predicted pathologic response outcomes in about 79% of patients based on plasma collected before and after cycle 1 of chemotherapy.  Dr. Neeraj Agarwal: This is so encouraging. It is such great news for our patients. So, what is the key takeaway from this trial?  Dr. Jeanny Aragon-Ching: Yeah, so I think the key takeaway from this abstract is that once validated, these cell-free DNA methylation patterns may be hopefully used to predict treatment response in patients with bladder cancer receiving neoadjuvant chemotherapy.  Now following validation of these results, we will hopefully be able to personalize neoadjuvant therapy for patients with localized muscle-invasive bladder cancer, and hopefully, improve the acceptability of this therapeutic modality in our clinics.  So, finally, moving forward with the last abstract that we would like to discuss today is Abstract 5018. It's called the BRCAAway trial. A randomized phase 2 trial of abiraterone, olaparib, or abiraterone with olaparib in patients with metastatic CRPC with DNA repair defects. What are your thoughts, Neeraj, on this one?  Dr. Neeraj Agarwal: As we have all seen over the last few years several PARP inhibitors have been approved or are in advanced phases of development for the treatment of patients with metastatic prostate cancer, both in the castrate-resistant phase as well as in hormone-sensitive setting, specifically those patients which are harboring germline or somatic mutations in homologous recombination repair genes.  We also know based on multiple reports that PARP 1 protein interacts with the androgen signaling pathway and concurrent or co-targeting of androgen receptors and one PARP pathway may have synergy.  The current study led by Dr. Maha Hussain addressed a pivotal question, are PARP inhibitors most effective as monotherapy or in combination with a novel androgen access inhibitor like abiraterone?  BRCAAaway is a randomized phase 2 trial of abiraterone or olaparib or abiraterone plus olaparib in patients with metastatic castrate-resistant prostate cancer, harboring inactivating alterations in BRCA1, BRCA2, and/or ATM genes.  This aspect of the trial is unique as none of the current trials have randomly assigned patients from monotherapy with a PARP inhibitor to monotherapy with a novel androgen axis inhibitor in the first line mCRPC setting.  The primary endpoint is progression-free survival, analyzed per Kaplan-Meier and Cox regression with multiple secondary endpoints. Both monotherapy arms were allowed to crossover at the time of progression. The 12-month progression-free survival was significantly improved with the 95% of patients treated on the combination of abiraterone prednisone plus olaparib arm, remaining on the protocol treatment compared to only 42% of patients on Abiraterone Prednisone arm or only 44% patients on the olaparib arm.  So, we saw a 12-month progression-free survival rate of almost double with a combination of abiraterone plus olaparib versus either of the monotherapies. And hence we can say that the PFS was significantly improved in combination therapy versus the monotherapy arm. And in addition, PSA response rates were also improved in the combination therapy arm.  Dr. Jeanny Aragon-Ching: So, this was really an important trial. So, what do you think is the key takeaway from this trial?  Dr. Neeraj Agarwal: The key takeaway from this abstract is that the combination of abiraterone, prednisone, plus olaparib was not only well tolerated, but was also associated with significantly improved progression-free survival and better PSA response rates compared to either agent alone. And this provides the rationale for using combination-based therapies rather than sequencing.  And obviously, this is a small trial, the data have to be validated in larger trials. But based on the fact that half of the prostate cancer patients who have advanced prostate cancer do not see subsequent lines of therapy is based on real-world results. The fact that combination therapy is so well tolerated and shows such significantly improved progression-free survival, I think these data are very encouraging for other trials, which are ongoing and may provide a solid rationale for combining these therapies rather than sequencing these therapies upfront.  So, Jeanny, any final thoughts? I think we have covered many of the important practices and influencing oral abstracts on the genitourinary sessions from the 2022 ASCO Annual Meeting. Obviously, we cannot cover all of them. There are many more we have left out. Having said that, any final thoughts before we wrap up our podcast today?  Dr. Jeanny Aragon-Ching: No, I think these are very interesting and very important abstracts that we discussed today. It's really a great way to wrap up the ASCO Annual Meeting for the GU section.  Dr. Neeraj Agarwal: Well, Jeanny, thank you for sharing all your insights with us today. It has been great discussing these abstracts with you.  Dr. Jeanny Aragon-Ching: Yeah, my pleasure, Neeraj.  Dr. Neeraj Agarwal: And thank you to our listeners for joining us today. You will find a link to the abstracts discussed today on the transcripts of this episode. Finally, if you value insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you very much!    Disclosures:  Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Medivation/Astellas, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, Gilead Sciences  Research Funding (Inst.): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck , Lilly, Nektar, ORIC Pharmaceuticals, crispr therapeutics, Arvinas  Dr. Jeanny Aragon-Ching:  Honoraria: Bristol-Myers Squibb , EMD Serono, Astellas Scientific and Medical Affairs Inc  Consulting or Advisory Role: Algeta/Bayer, Dendreon, AstraZeneca, Janssen Biotech, Sanofi, EMD Serono, AstraZeneca/MedImmune, Bayer, Merck, Seattle Genetics, Pfizer, Immunomedics, Amgen, AVEO, Pfizer/Myovant, Exelixis  Speakers' Bureau: Astellas Pharma, Janssen-Ortho, Bristol-Myers Squibb, Astellas/Seattle Genetics  Travel, Accommodations, Expenses: Dendreon,  Algeta/Bayer, Bristol Myers Squibb, EMD Serono , Astellas Pharma  Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.