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Christopher Wallis: Hello and thank you for joining us for this UroToday Journal Club discussion. Today, we're discussing a recent publication entitled, Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. I'm Chris Wallis, an Assistant Professor in the Division of Urology. With me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia. You see here, the citation for this recent publication of the PROpel trial recently published June 3rd in the New England Journal of Medicine Evidence.

The field of mCRPC has evolved fairly dramatically over the last, almost, two decades, with the introduction of a whole number of treatment approaches. Interestingly, to date, all of these have been utilized in the monotherapy setting and we have not yet seen successful trials of combination therapy in this disease space. You can see here that we get treatment sequencing as a result instead of treatment combinations, and there are a whole variety of treatment sequences that have been employed based on first-line therapies used. In randomized trials, median overall survivals approximately 3 years, but in real-world practice, overall survival is somewhat shorter following a diagnosis of mCRPC and real-world evidence has also shown us that many patients only receive a single line of mCRPC therapy, thus moving from monotherapy combination therapy may offer significant benefit of patients who are only going to get one treatment course.

One of the newer treatments used in mCRPC is PARP inhibitors, and we see here the two pivotal publications of the PROfound trial, assessing the role of olaparib in mCRPC. In the subset of patients with BRCA1, BRCA2, and ATM mutations here in cohort A, we see a fairly significant improvement in overall survival, with a hazard ratio of 0.69 and significant P-value 0.02. When we go to the whole cohort of biomarker-selected patients, we see a similar effect, although this was no longer statistically significant.

There is a rationale for combining PARP inhibitors with next-generation hormonal agents on the basis of two observations. The first is that PARP is involved in androgen receptor signaling, therefore co-inhibition of PARP may actually enhance androgen receptor targeting gene expression. A second is the converse, which is that next-generation androgen receptor signaling agents may inhibit homologous recombination repair gene transcription, and as a result, the use of these and NHTs may induce HRR deficiency leading to increase PARP inhibitor sensitivity. Thus, each agent may actually increase the sensitivity of tumors to the other agent. This was assessed first in a randomized phase II trial led by the same author group, which, as you can see here, demonstrated, or at least suggested, improvements with the combination compared to abiraterone alone.

This led to the design of the PROpel study. It is a phase III double-blind, randomized controlled trial comparing abiraterone plus olaparib to olaparib plus placebo as first-line therapy in mCRPC. The authors included adult men with histologically or cytologically confirmed prostate cancer who had at least one metastatic lesion on conventional imaging with CT and bone scan. Patients were allowed ADT as well as a first-generation antiandrogen, and they could have received prior docetaxel for mHSPC or could not have received prior abiraterone.

Patients were randomized in a 1:1 fashion into the two treatment arms. Treatment was delivered at standard doses with abiraterone 1000 milligrams PO once daily and olaparib 300 milligrams PO twice daily. Prednisone or prednisolone was given 5 milligrams PO twice daily to all patients. Randomization was stratified by metastasis type as well as the use of docetaxel in the castration-sensitive setting. Treatment was continued until the disease progressed or there was unacceptable toxicity or withdrawal of consent. Following progression, treatment was provided at the investigator's discretion.

The primary outcome was imaging-based progression-free survival, what the authors term ibPFS. The primary analysis of this was investigator initiated and a sensitivity analysis was performed using blinded independent central review. Secondary outcomes included overall survival, time to first subsequent therapy, time to second progression, and health related quality of life. Biomarker testing was not a mandated portion of enrollment in this study, unlike PROfound, for example, however, tumor and blood were collected at baseline and tumor was assessed using the FoundationOne CDX platform, whereas blood was assessed using the FoundationOne Liquid CDX platform. The following homologous recombination repair mutations were assessed. Notably, this is essentially the same as PROfound, although one of the mutations in which olaparib for was not efficacious in PROfound was dropped. Patients on the basis of this were categorized as HRR-mutant, non-HRR-mutant, or HR mutation status unknown.

The authors performed efficacy analysis in the intention-to-treat population and safety analyses in all exposed patients. The target sample size was 796 patients, with the planned first analysis at 379 imaging-based progression-free survival events, which gives approximately 48% maturity. This would allow 94% power for one-sided alpha 0.014, assuming a hazard ratio of 0.68. The authors use multiplicity testing for group sequential trials, with an overall familywise one-sided alpha of 0.025, and hierarchical testing of overall survival performed only where imaging-based progression-free survival showed positivity. O'Brien and Fleming spending function was used to control the overall type I error, and Kaplan-Meier analyses, as well as Cox proportional-hazards models, were used to assess their time to event outcomes. At this point in time, I'm going to hand it over to Zach to walk us through the results of the PROpel study.

Zachary Klaassen: Thanks so much, Chris, for the great introduction. This is the trial's characteristics of patients at baseline. As you can see here, the placebo group was on the right and olaparib group is to the left. We can see here that, essentially, the age was similar at 69 years of age in the olaparib group and 70 years of age in the placebo group. About two-thirds of patients had Gleason score greater than are equal to 8, and the majority of these patients had excellent performance status. All of them ECOG 0/1, with almost three-quarters of them being ECOG 0. In terms of prior docetaxel treatment, about one-quarter of these patients had prior chemo and the majority of this chemo was received at the metastatic hormone-sensitive prostate cancer stage.

With regard to disease site, bone metastases was by far the most common, with over 85% having bone mets, about one-third of patients have distant lymph node metastases, and about 20% of these have local regional lymph nodes. With regards to homologous recombination repair mutation status, about one-quarter to almost one-third had a mutation, with the remainder having no definitive mutation. With regards to BRCA mutations, majority of these patients that had a mutation were BRCA2.

The next several slides will highlight several Kaplan-Meier curves and the color scheme will be the same for both. The placebo group will be in red and the abiraterone plus olaparib group will be in blue. This is the primary outcome with the Kaplan-Meier curve looking at imaging-based progression-free survival from the investigator assessment. Median PFS in this assessment was 24.8 months for olaparib and 16.6 months for placebo, with a hazard ratio of 0.66 and a significant confidence interval 0.54 to 0.81. This is the sensitivity analysis looking at blinded independent central review for imaging-based PFS, with a median PFS of 27.6 months for the olaparib group and 16.4 months for the placebo group, and a significant hazard ratio of 0.61 and a 95% confidence in interval 0.49 to 0.74.

This is the forest plot of the subgroup analysis for the primary outcome of imaging-based PFS. We can see here, essentially, with the dotted line being a hazard ratio of 1 and to the left of the dotted line favoring olaparib, the majority of these subgroups benefited with abiraterone plus olaparib. I will make note that there was no benefit noted for black or African American race. However, as is seen in majority of these phase III clinical trials, the accrual of Black or African American men was quite low.

This Kaplan-Meier looks at the homologous recombination repair mutation subgroup looking at imaging-based PFS by investigator assessment. This was not reached as a median PFS for the olaparib group, and 13.9 months median PFS for the placebo group, with a hazard ratio of 0.5 and a significant confidence interval of 0.34 to 0.73. This is the same group up by blinded independent central review. Median PFS for olaparib was 28.8 months compared to 13.8 for the placebo group, with a hazard ratio, again significant, 0.45, 95% confidence interval, 0.31 to 0.65.

Switching over to the non-homologous recombination repair mutation group by investigator assessment imaging-based PFS. Median PFS for olaparib was 24.1 months compared to 19 months for placebo, with a hazard ratio of 0.76, 95% confidence interval, statistically significant, of 0.60 to 0.97. This is an important slide, as this shows that all-comers, regardless of their mutation status, received a benefit from abiraterone plus olaparib.

This is the same group BUT by blinded independent central review, again, showing a benefit for olaparib. Median PFS, 27.6, compared to placebo, 19.1 months, and a hazard ratio of 0.72 and a 95% confidence interval of 0.56 to 0.93. Moving on to secondary outcomes, this is the overall survival Kaplan-Meier curve, the median of which was not reached for both of these groups at a non-significant hazard ratio of 0.86, 95% confidence interval, 0.66 to 1.12.

This is time to first subsequent therapy, which was median of 25 months for the olaparib group and 19.9 months for the placebo group, which was significant. Hazard ratio of 0.74, 95% confidence interval of 0.61 to 0.90. The final Kaplan-Meier curve looks at PFS2 by investigator assessment, both of which the medium was not reached in either group, but the hazard ratio was significant favoring abiraterone plus olaparib at 0.69 and a 95% confidence interval of 0.51 to 0.94.

Looking at the treatment-emergent adverse events, as you would expect, all patients essentially had some adverse event of any grade. However, there was slightly more adverse events in the olaparib group, at 47.2% for grade greater than equal to 3, compared to 38.4% for patients getting abiraterone and placebo. Several treatment-emergent adverse events of note, you can see here, anemia for the olaparib group, 15.1% grade greater than equal to 3, compared to 3.3% in the placebo group, as well as, of note, venous embolic and thrombotic events, 6.8% grade group 3 or greater for the olaparib group compared to 2% for the abiraterone plus placebo group.

Several discussion points from the PROpel trial. This trial did meet its primary endpoint, which was showing that treatment with abiraterone plus olaparib significantly prolonged imaging based PFS compared to abiraterone plus placebo. Because enrollment was not based on biomarker status, patients were representative of those eligible for abiraterone in the real-world setting without restricting therapy to patients for whom mutation status could not be assigned. These findings validate the radiographic progression-free survival results of an earlier phase II trial of abiraterone plus olaparib versus abiraterone plus placebo in patients with mCRPC who had previously received docetaxel, and this hazard ratio was 0.65, with a 95% confidence interval of 0.44 to 0.97.

In conclusion, at the time of the primary analysis at the first data cutoff, abiraterone plus olaparib led to significantly longer imaging-based PFS compared to abiraterone plus placebo in patients with mCRPC. As mentioned, this was enrolled irrespective of their mutation status and these patients had not received treatment in the first-line setting. OS did not reach pre-specified threshold for significance. However, this is data that's only 28.6% mature. Finally, the overall results of PROpel demonstrate the clinical benefits of olaparib in combination with abiraterone in the first-line treatment of a broad, recombination mutation unselected population of patients with mCRPC. Thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of the PROpel trial.