FDA Grants Priority Review to Olaparib/Abiraterone Regimen in Metastatic Castration-Resistant Prostate Cancer


The FDA has granted priority review to a supplemental new drug application seeking the approval of olaparib in combination with abiraterone acetate and prednisone or prednisolone in adult patients with metastatic castration-resistant prostate cancer.



The FDA has granted priority review to a supplemental new drug application (sNDA) seeking the approval of olaparib (Lynparza) in combination with abiraterone acetate (Zytiga) and prednisone or prednisolone in adult patients with metastatic castration-resistant prostate cancer (mCRPC).1

The application is supported by findings from the phase 3 PROpel trial (NCT03732820), in which the olaparib plus abiraterone and prednisone or prednisolone (n = 399) significantly prolonged imaging-based progression-free survival (ibPFS) vs placebo plus abiraterone and prednisone or prednisolone (n = 397), at 24.8 months vs 16.6 months, respectively (HR, 0.66; 95% CI, 0.54-0.81; P < .001).2 These data proved to be consistent with what was observed with blinded independent central review (HR, 0.61; 95% CI, 0.49-0.74).

Under the Prescription Drug User Fee Act, the regulatory agency is expected to decide on the sNDA in the fourth quarter of 2022.

“There remains a critical unmet need among patients diagnosed with metastatic castration-resistant prostate cancer, where the prognosis remains poor and treatment options are limited,” Susan Galbraith, executive vice president of Oncology R&D, at AstraZeneca, stated in a press release. “Today’s news is another step toward bringing forward a new, much-needed treatment option in this setting. If approved, Lynparza with abiraterone will become the first combination of a PARP inhibitor and a new hormonal agent for patients with this disease.”

The double-blind, placebo-controlled trial enrolled patients with histologically or cytologically confirmed prostate adenocarcinoma with at least 1 documented metastatic lesion on a bone scan or computed tomography or magnetic resonance imaging scan. Patients needed to be at least 18 years of age, and they could not have previously received systemic treatment in the frontline setting except for androgen deprivation therapy and first-generation antiandrogen agents with a 4-week washout period.

Study participants were randomly assigned 1:1 to receive abiraterone at a once daily dose of 1000 mg plus olaparib at a twice daily dose of 300 mg or placebo. All patients were given prednisone or prednisolone at a twice daily dose of 5 mg per the abiraterone label requirement. Treatment was given until disease progression, intolerable toxicity, or withdrawn consent. After progression, further treatment was decided based on investigator discretion.

Stratification factors included distant metastasis type at baseline (bone only vs visceral vs other) and by docetaxel treatment at the metastatic stage of disease (yes vs no).

The primary end point of the trial was ibPFS per investigator assessment. Investigators also conducted a sensitivity analysis by blinded independent central review of imaging and an exploratory subgroup analysis of investigator-assessed ibPFS. In the subgroup analysis, treatment effect consistency was examined across prespecified prognostic factors of importance.

Overall survival (OS) served as a key secondary end point, as well as time to first subsequent therapy (TFST) or death, time to second progression or death (PFS2), and health-related quality of life. Exploratory end points included objective response rate (ORR), prostate-specific antigen (PSA) response rate, and time to PSA progression.

Baseline characteristics were noted to be balanced between the treatment arms. The median age of those in the investigative arm was 69.0 years (range, 43-91) vs 70.0 years (range, 46-88) in the control arm. Most patients in the olaparib and placebo arms had an ECOG performance status of 0 (71.7% vs 68.5%, respectively), disease in the bone (87.5% vs 85.4%), and no homologous recombination repair (HRR) gene mutation (69.9% vs 68.8%).

Moreover, 24.3% of those in the olaparib arm received prior docetaxel vs 24.7% of those in the placebo arm; 22.6% and 22.4% of patients, respectively, received the agent at the metastatic hormone-sensitive disease stage. Regarding BRCA mutational prevalence, 2.3% of those on the olaparib arm harbored BRCA1 mutations vs 0.8% of those on the placebo arm; 9.5% and 8.8% of patients, respectively, harbored BRCA2 mutations.

The data cutoff for the data published in NEJM Evidence was July 30, 2021. Additional data showed that an ibPFS benefit with olaparib over placebo was noted across all prespecified subsets, irrespective of whether it was done via investigator assessment or by blinded independent central review. A consistent treatment effect was reported between the subgroups

A total of 226 patients comprised the HRR-mutated population; 90 patients tested positive via tumor tissue and circulating tumor DNA (ctDNA), 28 by tumor tissue, and 108 by ctDNA. A total of 552 patients comprised the non–HRR-mutated population; 328 of these patients were negative by tumor tissue and ctDNA, 38 by tumor tissue, and 186 by ctDNA.

Notably, all hazard ratios (HRs) for both populations were noted to favor the olaparib combination arm compared with the placebo arm. The HR in the HRR-mutated group for ibPFS by investigator assessment was 0.50 (95% CI, 0.34-0.73); in the non–HRR-mutated group, the HR for ibPFS was 0.76 (95% CI, 0.60-0.97).

The OS data were still immature at the time of the primary analysis, with 28.6% maturity (HR, 0.86; 95% CI, 0.66-1.12; P = .29). Notably, however, TFST (HR, 0.74; 95% CI, 0.61-0.90) and PFS2 (HR, 0.69; 95% CI, 0.51-0.94) data supported an efficacy beyond first imaging-based disease progression.

Among those with measurable disease at baseline, the olaparib/abiraterone combination (n = 161) elicited an ORR of 40.3% vs 48.1% with abiraterone/placebo (n = 160; odds ratio, 1.60; 95% CI, 1.02-2.53). Moreover, the confirmed PSA response in the investigative and control arms were 79.3% and 69.2%, respectively. The median time to PSA progression had not yet been reached in the olaparib arm vs 12.0 months in the placebo arm (HR, 0.55; 95% CI, 0.45-0.68).

The safety and tolerability of olaparib plus abiraterone was consistent with what has previously been observed and aligned with the known toxicity profiles of each medicine.


  1. Lynparza in combination with abiraterone granted priority review in the US for patients with metastatic castration-resistant prostate cancer. News release. AstraZeneca. August 16, 2022. Accessed August 16, 2022. https://bit.ly/3Pw4Lhs
  2. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, et al. Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evidence. Published online June 3, 2022. doi:10.1056/EVIDoa2200043
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