FDA Approves Olaparib for HRR Gene–Mutated Metastatic Castration-Resistant Prostate Cancer

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On May 19, the U.S. Food and Drug Administration (FDA) approved olaparib (Lynparza) for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated metastatic castration-resistant prostate cancer who have had disease progression following prior treatment with enzalutamide or abiraterone.

The FDA also approved FoundationOne CDx for the selection of patients with metastatic castration-resistant prostate cancer carrying HRR gene alterations and the BRACAnalysis CDx test for selection of patients with metastatic castration-resistant prostate cancer carrying germline BRCA1/2 alterations as companion diagnostic devices for treatment with olaparib.  

PROfound Study

Efficacy was investigated in PROfound, an open-label, multicenter trial that randomly assigned 256 patients to treatment with olaparib at 300 mg twice daily, and 131 patients to investigator’s choice of enzalutamide or abiraterone acetate. All patients received a gonadotropin-releasing hormone analog or had prior bilateral orchiectomy.

Patients were divided into two cohorts based on their HRR gene mutation status. Patients with mutations in either BRCA1BRCA2, or ATM were randomly assigned to cohort A (n = 245); patients with mutations among 12 other genes involved in the HRR pathway were randomly assigned to cohort B (n = 142); those with comutations (cohort A gene and a cohort B gene) were assigned to cohort A.

The major efficacy outcome of the trial was radiologic progression-free survival (rPFS, cohort A). Additional efficacy outcomes included confirmed objective response rate (cohort A) in patients with measurable disease, rPFS for combined cohorts A and B, and overall survival (cohort A).

A statistically significant improvement was demonstrated for olaparib compared to investigator’s choice in cohort A for rPFS, with a median of 7.4 months vs 3.6 months (hazard ratio [HR] = 0.34, 95% confidence interval [CI] = 0.25–0.47, P < .0001). A statistically significant improvement was also demonstrated for overall survival, with a median of 19.1 months vs. 14.7 months (HR = 0.69, 95% CI = 0.50–0.97, P = .0175), and for objective response rate: 33% vs 2% (P < .0001). A statistically significant improvement for olaparib compared to investigator’s choice was also demonstrated for rPFS in combined cohorts A and B, with a median of 5.8 months vs. 3.5 months (HR = 0.49, 95% CI = 0.38–0.63, P < .0001).

The most common adverse reactions seen in PROfound with olaparib (≥ 10% of patients) were anemia, nausea, fatigue (including asthenia), decreased appetite, diarrhea, vomiting, thrombocytopenia, cough, and dyspnea. Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients randomly assigned to the olaparib arm compared to 3.1% of those receiving enzalutamide or abiraterone.

The recommended olaparib dose is 300 mg taken orally twice daily, with or without food.


The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.