#GU22: Learning From the PROpel and MAGNITUDE Trials

Dr. Neeraj Agarwal, ASCO Daily News editor-in-chief, and director of the Genitourinary Cancers Program at the University of Utah’s Huntsman Cancer Institute, shares key takeaways from the PROpel and MAGNITUDE trials in mCRPC, featured at the 2022 ASCO Genitourinary Cancers Symposium.   Transcript: ASCO Daily News: Hello and welcome to the ASCO Daily News Podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. Today, in our continuing coverage of the 2022 ASCO Genitourinary (GU) Cancers Symposium, Dr. Neeraj Agarwal, the editor-in-chief of the ASCO Daily News will highlight promising advances in metastatic castration-resistant prostate cancer. Dr. Agarwal has no conflicts relating to the topic of this episode, and his full disclosures are available in the show notes. Disclosures of all guests on the podcast can be found in our transcripts at asco.org/podcasts.   Dr. Neeraj Agarwal: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Neeraj Agarwal, the director of the Genitourinary Cancer Program, and professor of medicine at the University of Utah Huntsman Cancer Institute, and editor in chief of the ASCO Daily News. I'd like to start with the PROpel trial followed by a discussion on the MAGNITUDE trial. So, Abstract 11 was on the results of the PROpel trial and presented by Dr. Fred Saad from the University of Montreal. PROpel is a randomized phase 3 trial, which evaluated the efficacy and safety of olaparib, a PARP inhibitor plus abiraterone versus this placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer setting. Patients were allowed to have docetaxel chemotherapy is given in a metastatic castration-sensitive prostate cancer setting. Enrollment in the study was independent of the effects in the homologous recombination repair pathway. The primary endpoint was investigator-assessed radiographic progression-free survival (PFS) with multiple secondary endpoints, including overall survival and safety.   Approximately 800 patients were randomly assigned to the novel combination of olaparib plus abiraterone or placebo plus abiraterone. Baseline characteristics were well-balanced between the treatment arms, including homologous recombination repair or HRR mutation status. At the pre-planned interim analysis results show the trial meets its primary endpoint with significant improvement in radiographic PFS for all patients receiving the combination therapy versus control, regardless of the presence of homologous recombination repair gene mutations. Median PFS was 24.8 months versus 16.6 months for patients receiving olaparib plus abiraterone versus placebo plus abiraterone respectively with the hazard ratio of 0.66, and a P < 0.0001. This translates into a 34% reduction in risk of progression or death. Overall survival results are still immature with only 29% [of patients experiencing events] thus far. It is interesting that even patients deemed negative for homologous recombination repair gene mutations showed significant improvement in radiographic PFS when treated with the combination of olaparib plus abiraterone versus placebo plus abiraterone.   Regarding the adverse effects, they were what you would expect from the combination of a PARP inhibitor, such as olaparib and abiraterone. We saw a higher sequence of all great events of anemia, fatigue, and nausea in the combination arm. While anemia was the only grade 3-4 adverse event observed at a significantly high frequency in the combination arm. It is also important [that] we get a better understanding of the molecular mechanism by which patients who are homologous recombination repair mutation-negative are benefiting from the combination treatment as well.   The next trial in this context, or this team, was the MAGNITUDE trial. Abstract 12 was presented by Dr. Kim Chi from British Columbia Cancer Center in Vancouver, Canada. MAGNITUDE is a randomized phase 3 trial evaluating the efficacy and safety of niraparib plus abiraterone plus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer setting. The study population was slightly different from what we saw in PROpel trial. Taxane chemotherapy, as well as novel hormonal therapy, was allowed in metastatic castration-sensitive prostate cancer, as well as a prior novel hormonal therapy was allowed in the non-metastatic castration-resistant prostate cancer.   Also, patients were allowed up to 4 months of treatment with abiraterone in the first-line metastatic castrate-resistant prostate cancer. Prospective selection of patients with, and without homologous recombination repair (HRR) gene mutations were required. The primary endpoint was radiographic PFS by central review with multiple secondary endpoints, including overall survival and safety. A pre-specified fertility analysis was planned after enrolling 233 patients who were randomly assigned to niraparib plus abiraterone or placebo plus abiraterone. Evaluation of fertility was based on the composite PFS of PSA or radiographic progression, whichever occurred first. The pre-planned fertility analysis showed no benefit in the biomarker negative cohort. And thus the trial did not pursue further enrollment of those patients who were not positive for homologous recombination repair gene mutations.   Coming to the HRR positive cohort, 423 patients were randomly assigned to either niraparib plus abiraterone or placebo plus abiraterone. At the pre-planned interim analysis primary endpoint was met with a significant improvement in radiographic PFS for BRCA1 and BRCA2 and all patients who are homologous recombination repair mutation-positive, receiving the novel combination of niraparib plus abiraterone. Overall survival results are still immature. It is important to note that in the patients who are HRR positive, approximately 50% were BRCA1 and 2 positive. And these patients clearly derived the most benefit with a combination with an approximate 47% reduced risk of death. And if you look at other patients who are biomarker positive, there was a clear benefit and a significant improvement in median PFS (radiographic progression-free survival) with a hazard ratio of 0.73, which translates to a 27% reduction in the risk of death or progression. With the caveat of subgroup analysis, being underpowered following groups of patients seem to derive less benefit with the combination than the overall cohort with the combination of niraparib plus abiraterone. And these patients included patients who were age 65 or younger, or less than age 65, patients with visceral metastatic disease, patients with prior abiraterone or taxane chemotherapy, [and] patients who had a PSL level below the median, and patients with non-BRCA homologous recombination repair mutations.   In conclusion, the combination of niraparib plus abiraterone shows a significant improvement in the radiographic PFS for patients who are HRR positive in the first-line metastatic CRPC. Based on the available data in the public domain, without any doubt that both PROpel and MAGNITUDE trials established a combination of a PARP inhibitor with abiraterone in the first-line metastatic CRPC setting for patients who are positive for HRR mutation improve radiographic progression-free survival. Even though overall survival data are immature for both trials, I expect both combinations will be approved by the U.S. Food and Drug Administration in the near future and will be available to our patients. Regarding the HRR negative cohort in the PROpel trial, which also seems to derive significant benefit with the combination of abiraterone plus olaparib, I'm looking forward to the data on confirmation of HRR negative status by tissue-based genomic profiling results in the full-length publication which we expect to be published soon. If indeed confirmed by the tissue-based genomic profiling, I see the combination of abiraterone plus olaparib to be a reasonable option in the patients who are HRR negative in the first-line metastatic CRPC setting.   With this, I would like to conclude my discussion on the 2 practice-changing trials presented in the 2022 ASCO GU meeting, which were the PROpel and MAGNITUDE trials. Thank you very much for your kind attention. ASCO Daily News: That was Dr. Neeraj Agarwal of the University of Utah's Huntsman Cancer Institute. Thanks for joining us today. If you're enjoying the content on the podcast, please take a moment to rate and review us wherever you get your podcast.   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, Merck, Novartis, lily, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, ORIC Pharmaceuticals, CRISPR therapeutics, and Arvinas Disclaimer: The purpose of this podcast is to educate and to inform. 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