Olaparib Combo Does Not Yield Significant OS Benefit Vs Placebo in mCRPC

“No new safety signals were identified with longer follow-up and no change in health-related quality of life [HRQOL] as assessed by FACT-P Total Score was observed with the addition of olaparib to abiraterone," according to the authors of the phase 3 PROpel trial (NCT03732820).

The addition of olaparib (Lynparza) to abiraterone acetate (Zytiga) and prednisone or prednisolone did not achieve significant differences in overall survival (OS) compared with placebo plus abiraterone acetate and prednisone or prednisolone among patients with metastatic castration-resistant prostate cancer (CRPC), according to final prespecified analysis findings from the phase 3 PROpel trial (NCT03732820).

Investigators highlighted a median OS of 42.1 months (95% CI, 38.4-not reached [NR]) in the olaparib arm compared with 34.7 months (95% CI, 31.0-39.3) in the placebo arm (HR, 0.81; 95% CI, 0.67-1.00; P = .054).

The median time to first subsequent therapy for patients in the olaparib and placebo arms, respectively, were 24.6 months (95% CI, 21.1-28.5) vs 19.4 months (95% CI, 17.0-21.1; HR, 0.76; 95% CI, 0.64-0.90). Additionally, the median time to second progression or death was not reached in either treatment arm (HR, 0.76; 95% CI, 0.59-0.99). Investigators reported a median time to prostate-specific antigen progression of 24.2 months (95% CI, 18.5-29.4) vs 12.0 months (95% CI, 11.0-13.8) in each respective arm (HR, 0.59; 95% CI, 0.49-0.71).

Treatment with the olaparib-based regimen previously produced a significant improvement in the primary end point of radiographic progression-free survival (rPFS) as reported in an earlier analysis. According to the investigators, rPFS outcomes in the PROpel trial’s final prespecified analysis were comparable with findings highlighted in the primary analysis.

“Aggregate biomarker subgroup analyses generally favored olaparib plus abiraterone, with homologous recombination repair [HRR] mutations and BRCA-mutated patients having greater benefit than those without these mutations,” the study authors wrote. “No new safety signals were identified with longer follow-up and no change in health-related quality of life [HRQOL] as assessed by FACT-P Total Score was observed with the addition of olaparib to abiraterone.”

Patients enrolled on the PROpel trial were randomly assigned 1:1 to receive 300 mg of olaparib twice a day (n = 399) or matched placebo (n = 397) plus 1000 mg of abiraterone acetate orally once a day and prednisone or prednisolone at 5 mg twice a day.

The trial’s primary end point was rPFS per investigator assessment based on RECIST v1.1 criteria. Secondary end points included OS, time to first subsequent therapy or death, time to second progression or death, and HRQOL.

Patients 18 years and older with histologically or cytologically confirmed prostate adenocarcinoma with 1 or more metastatic lesions were able to enroll on the trial. Additional eligibility criteria included an ECOG performance status of 0 or 1 and a minimum life expectancy of 6 months.

Most patients in the olaparib and placebo arms, respectively, had a Gleason score of 8 or higher (66% vs 65%), disease located in the bone (87% vs 85%), and no HRR mutations per ctDNA testing (67% vs 67%) and tumor tissue testing (52% vs 53%). Additionally, most patients in each arm were White (71% vs 69%) and not Hispanic (78% vs 77%).

The median duration of treatment exposure was 18.5 months (interquartile range [IQR], 7.4-33.8) with olaparib, 15.7 months (IQR, 8.1-29.6) with placebo, 20.1 months (IQR, 8.5-34.2) with abiraterone in the olaparib arm, and 15.7 months (IQR, 8.0-30.3) with abiraterone in the placebo arm. Investigators noted that there were no new safety signals in the final prespecified analysis.

In the olaparib and placebo arms, respectively, any-grade adverse effects (AEs) affected 98% and 96% of patients. The most common grade 3/4 AE was anemia, which was reported in 16% and 3% of patients in each respective arm. Additionally, serious AEs occurred in 40% and 32% of patients in the experiment and control arms, respectively; the most common toxicity was anemia (6% vs 1%).

Overall, 17% of patients who received olaparib and 9% of those treated with placebo discontinued their respective therapies following AEs. Moreover, 7% and 2% of patients in each respective arm experienced cardiovascular AEs. Investigators noted 1 treatment-related death in the placebo arm due to interstitial lung disease.

Reference

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. Lancet Oncol. 2023;24:1094-1108. doi:10.1016/S1470-2045(23)00382-0