OS Analysis of PROpel Maintains Efficacy of Olaparib/Abiraterone in mCRPC

Fred Saad, MD, FRSC

At the final prespecified analysis of the PROpel study (NCT03732820), overall survival (OS) was not significantly different between patients with first-line metastatic castration-resistant prostate cancer (mCRPC) unselected by homologous recombination repair mutation (HRRm) status who were treated with olaparib (Lynparza) plus abiraterone acetate (Zytiga) vs placebo plus abiraterone.¹

According to data from the final prespecified OS analysis, the median follow-up for OS in patients with censored data in the olaparib plus abiraterone arm was 36.6 months (interquartile range, 34.1-40.3) vs 36.5 months (33.8-40.3) in the placebo plus abiraterone arm.

With the olaparib combination, the median OS was 42.1 months (95% CI, 38.4-not reached) compared with 34.7 months (31.0-39.3) with placebo plus abiraterone (HR, 0.81; 95% CI, 0.67-1.00; P = .·054).

“This regimen [gives] an opportunity to offer more than what we could offer for patients that have lethal prostate cancer. We know that olaparib is effective if you've already failed a novel hormonal and have a BRCA mutation or an ATM mutation, but that is a very small subgroup. This is an opportunity to treat many more patients earlier, and make a big difference for those patients,” Fred Saad, MD, FRSC, director of prostate cancer research at Montreal Cancer Institute/CRCHUM, previously told Targeted Oncology^TM.

Prostate cancer, bladder cancer, men's health care: © Tom - stock.adobe.com

Previously, in May 2023, the FDA approved olaparib in combination with abiraterone and prednisone or prednisolone for adult patients with mCRPC as olaparib and abiraterone reduced the risk of progression or death by 34% in this patient population vs abiraterone in the PROpel study (HR, .066; 95% CI, 0.54-0.81; P < .0001).^2,3

The phase 3 PROpel study met its primary end point of radiographic progression-free survival (rPFS), showing a statistically significant improvement in the olaparib plus abiraterone arm vs placebo plus abiraterone arm.² Olaparib resulted in a median rPFS of 24.8 months vs 16.6 months with standard of care (HR, 0.66; 95% CI, 0.54-0.81; P <.0001) per investigator review.

The blinded independent central review confirmed these findings (HR, 0.61; 95% CI, 0.49-0.74; nominal P < .0001), and a benefit was observed in all prespecified subgroups. Further, the safety and tolerability profile of the combination observed in this study was consistent with prior clinical trial data and with what is known of the individual treatments.

The randomized, double-blind, phase 3 trial was performed at 126 centers in 17 countries globally and enrolled patients with mCRPC who were at least 18 years of age or older with an ECOG performance status 0-1, and a life expectancy of at least 6 months. Patients must not have received prior systemic treatment for mCRPC unselected by HRRm status.

Once enrolled, patients were randomly assigned in a 1:1 fashion to receive abiraterone acetate orally at a dose of 1000 mg once a day plus prednisone or prednisolone with either oral olaparib 300 mg twice daily or placebo. Patients were startfied by site of metastases and previous docetaxel at metastatic hormone-sensitive cancer stage.

In addition to the primary end point of rPFS, investigators evaluated OS as a key secondary end point with alpha-control evaluated in the intention-to-treat population. The study also evaluated the safety of the combination in all patients who received at least 1 dose of a study drug.

A total of 1103 patients were screened between October 31, 2018, and March 11, 2020, with 399 patients randomized to the olaparib plus abiraterone arm and 397 to the placebo plus abiraterone arm. At the time of the final analysis, 210 patients in the olaparib plus abiraterone group remained in the study, as did 178 in the placebo plus abiraterone group, and 110 and 79 patients remained on study treatment.

At baseline, demographic and clinical characteristics of those enrolled were similar between treatment groups. In the olaparib plus abiraterone group vs placebo plus abiraterone group, patients were a median age of 69 years (range, 63-74) vs 70 years (range, 65-76) of age, 66% vs 65% had a Gleason score of ≥8, 72% vs 69% had an ECOG performance status of 0, 24% vs 25% had received prior treated with docetaxel before mCRPC, and the majority of patients were White (71% v 69%) and not Hispanic or Latinx (78% v 77%).

Bone was the site of disease in 87% of patients in the olaparib combination arm vs 85% in the placebo arm, distant lymph nodes in 33% and 30%, locoregional lymph nodes in 21% and 22%, prostate and adjacent structures in 12% each, respiratory in 10% and 11%, and liver in 4% and 5%.

Regarding safety, the most common adverse event (AE) which was grade 3 or 4 was anemia in 16% of patients (n = 64) given olaparib plus abiraterone and 3% (n = 13) in the placebo plus abiraterone group. Among patients treated with olaparib and abiraterone, serious AEs were observed in 40% (n = 161) and 32% (n = 126) in the placebo plus abiraterone group, with anemia being the most common, reported in 6% (n = 23) and 1% (n = 3).

Seventeen percent (n = 69) of patients discontinued olaparib and 34 (9%) of 396 patients discontinued placebo due to an AE, and AEs led to death in 7% (n = 26) of patients in the olaparib combination group vs 5% (n = 20) in the placebo group. One patient died from interstitial lung disease in the placebo plus abiraterone group, and this death was considered treatment-related.

Further research is warranted to understand the clinical benefit of olaparib plus abiraterone in patients with mCRPC with and without HRR mutations.

“This is an opportunity to make a bigger difference in the lives of patients that are diagnosed with firstline mCRPC that have not yet been exposed to a novel hormonal therapy. We need to be able to advance the science and offer more to our patients,” added Saad.

REFERENCES:

1. Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial [published online ahead of print, 2023 Sep 12]. Lancet Oncol. 2023;S1470-2045(23)00382-0. doi:10.1016/S1470-2045(23)00382-0

2. Clarke NW, Armstrong AJ, Thiery Vuillemin A, et al; PROpel Investigators. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9). doi:10.1056/EVIDoa2200043

3. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. News release. FDA. October 4, 2023. Accessed May 31, 2023. https://tinyurl.com/352x6kad