Approximately 50% of patients with metastatic castration-resistance prostate cancer (mCRPC) receive only 1 line of active therapy with a median survival of less than 2 years.¹ Hence, there is an urgent need to improve patient outcomes in the first-line mCRPC treatment setting.¹ In the PROpel phase 3 trial, the administration of olaparib and abiraterone combination in mCRPC patients, irrespective of homologous recombination repair gene mutation (HRRm) status, has achieved statistically significant and clinically meaningful improvements in radiographic progression-free survival (rPFS) than abiraterone monotherapy alone.

Prostate cancer is the second leading cause of cancer death in men, claiming 375,000 lives in 2020.² The backbone of prostate cancer treatment is mainly based on different strategies to block androgen receptor signaling.³ Previously, a phase 2 trial showed increased rPFS in mCRPC patients treated with olaparib and abiraterone combination than abiraterone alone, irrespective of the HRRm status.¹ Similarly, a phase 3 trial of olaparib alone showed significantly improved overall survival (OS) and rPFS in patients with mCRPC post next-generation hormonal agent (NHA) with homologous recombination repair (HRR) gene alterations.¹

PROpel is a double-blind, phase 3 trial which equally randomized patients (N=796) to receive either olaparib (300mg; twice daily) and abiraterone (1,000mg; once daily) or placebo and abiraterone (1,000mg; once daily).¹ The primary endpoint of this study based on the investigator assessment revealed a 34% of risk reduction of progression or death with olaparib and abiraterone combination therapy (HR=0.66; 95% CI: 0.54-0.81; p<0.0001).¹ The median rPFS was 24.8 months and 16.6 months for olaparib/abiraterone combination therapy and abiraterone monotherapy, respectively.¹ The combination therapy treatment improved OS when compared with abiraterone alone. However, a statistically significant difference was not reached at the time of this data cut-off (analysis at 29% of data maturity).¹

Additional endpoints, such as time to first subsequent therapy (TFST) and second progression-free survival (PFS2), showed long-term benefits with the combination therapy.¹ The objective response rate (ORR) showed a 10% of improvement in the combination treatment when compared with monotherapy.¹ Data from the prostate-specific antigen levels and circulating-tumor-cell counts supported treatment benefits of the combination therapy in the overall population.¹

The combination therapy had an overall good safety and tolerability, similar to the safety of their known profile of individual drugs.1 Although cardiac failure and arterial thromboembolic events were similar between both groups, there was a minor increase in the venous thromboembolic events (pulmonary embolism) reported for the combination therapy.¹ The mean change from baseline in the Functional Assessment of Cancer Therapy-Prostate (FACT-P) scores reflected a comparable health-related quality of life between both treatment arms.¹

The authors stated that olaparib and abiraterone led to a significant and clinically meaningful improvement in rPFS (HR=0.66; 95% CI: 0.54-0.81) over placebo and abiraterone in first-line mCRPC. They further stated that the secondary and exploratory endpoints supported the treatment benefits of olaparib and abiraterone over placebo and abiraterone in the overall patient population.¹

To conclude, the PROpel trial took the first-ever combination approach to improve clinical benefits in patients in the first-line mCRPC setting, regardless of the HRRm status.