Fred Saad: Hello, I'm Professor Fred Saad from the University of Montreal, and on behalf of my co-authors, it's my pleasure to present a summary of the results from the PROpel trial of olaparib plus abiraterone versus placebo plus abiraterone in patients with first-line mCRPC.

PARP inhibitors such as olaparib have been in clinical use as monotherapy for HRR-mutated mCRPC since 2020. More recently, results from phase III studies of PARP inhibitors in combination with next-generation hormonal agents, or NHAs, have led to the approval of several new drug combinations globally for the treatment of mCRPC.

PROpel was the first phase III trial of a PARP inhibitor combined with an NHA in the treatment of patients with mCRPC. Patients were enrolled irrespective of homologous recombination repair, or HRR, gene mutation status based on results from the phase II Study 8, which demonstrated a statistically significant rPFS benefit with olaparib plus abiraterone versus placebo plus abiraterone in biomarker unselected patients with mCRPC who had progressed on prior docetaxel. Exploratory analysis from Study 8 also showed a benefit regardless of biomarker status.

PROpel investigated the combination of olaparib plus abiraterone in the first-line setting. It met its primary endpoint and demonstrated a statistically significant and clinically meaningful rPFS benefit with olaparib plus abiraterone versus placebo plus abiraterone, which is particularly notable given that abiraterone is a current life-prolonging standard of care treatment of first-line mCRPC. The median rPFS was 24.8 months in the olaparib plus abiraterone arm versus 16.6 months in the placebo plus abiraterone arm with a hazard ratio of 0.66. Sensitivity analysis for rPFS found hazard ratios favoring olaparib plus abiraterone in all pre-specified subgroup analyzed with notable benefits observed in some subgroups such as patients who are under 65 years of age, those with visceral metastases or patients having received docetaxel in the hormone-sensitive state.

Recently, we reported in the Lancet Oncology that at the time of final pre-specified OS analysis, median OS in the olaparib plus abiraterone arm was 42.1 months. Although not statistically significant, this is the longest overall survival seen to date in an mCRPC trial, representing a median overall survival up to 7.4 months longer than 34.7 months with abiraterone alone. This yielded a hazard ratio of 0.81 in favor of olaparib plus abiraterone. The length of median OS is particularly striking given that approximately one quarter of patients included in the PROpel trial were moderately or severely symptomatic at baseline.

Although patients in PROpel were not selected based on their HRR mutation status, tumor tissue and ctDNA were tested following randomization and prior to primary analysis to determine HRR status, including whether they had an ERCA mutation. Efficacy was then assessed for subgroups of patients both with and without a mutation. We observed a numerical rPFS and OS benefit for patients in the HRRm, non-HRRm, BRCAm, and non-BRCAm subgroups. The greatest efficacy benefit was observed in patients with a BRCA mutation as expected. In this subgroup, median overall survival was not reached versus 23 months with a hazard ratio of 0.29. This finding highlights the importance of biomarker testing for clinical decision-making, assessment of prognosis and familial risk.

Additional secondary and exploratory endpoints, such as time to first subsequent therapy or death, time to second progression or death and time to PSA progression also favored the combination of olaparib plus abiraterone and support the primary analysis. At primary analysis, the safety profile of olaparib plus abiraterone was consistent with the known safety profiles for the individual drugs. At final analysis, no new safety signals were observed and the most common adverse effect in the olaparib plus abiraterone arm were anemia, fatigue or asthenia and nausea. In the placebo plus abiraterone arm, the most common adverse events were fatigue or asthenia, back pain, and arthralgia. Anemia was also the most common grade 3 or 4 adverse event observed in the olaparib plus abiraterone arm occurring in 16% of patients. This is a lower rate of anemia that has been seen in other trials of PARP inhibitors combined with NHAs. However, we are not able to draw conclusions in the absence of head-to-head trials.

Although there were more grade 3+ adverse events in the olaparib plus abiraterone arm of the trial, no clinically meaningful effect on overall health-related quality of life based on the functional assessment of cancer therapy, prostate or FACT-P total score was observed when olaparib was added to the standard of care abiraterone treatment.

Understanding the goals of a patient and the benefit-risk profiles of different treatments is essential to support patient-physician discussions and shared decision-making. Results from PROpel show that there was an efficacy benefit with olaparib plus abiraterone versus placebo plus abiraterone in patients with and without HRR or BRCA mutations. This is important given that many mCRPC patients have unknown biomarker status. The safety profile of the combination was predictable and manageable and combining these drugs did not impact health-related quality of life. Overall, these findings support the consideration of olaparib plus abiraterone as a first-line treatment for patients with mCRPC.

My co-authors and I would like to thank all of the patients, their families and caregivers, and the investigators and staff who participated in this trial. Thank you.