On May 19, 2020, 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 (mCRPC), who have progressed following prior treatment with enzalutamide or abiraterone.

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

FDA also approved FoundationOne®CDx for selection of patients with mCRPC carrying HRR gene alterations and BRACAnalysis CDx® for selection of patients with mCRPC carrying germline BRCA1/2 alterations as companion diagnostic devices for treatment with olaparib. 

Efficacy was investigated in an open-label, multicenter trial (PROfound; NCT02987543) randomizing 387 patients 2:1 to receive 300 mg of olaparib 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. Investigators randomized patients with mutations in the BRCA1, BRCA2, or ATM genes in cohort A (n = 245) and patients with mutations among 12 other genes involved in the HRR pathway in cohort B (n = 142). Investigators assigned those with comutations to cohort A.

The major efficacy outcomes of cohort A were radiologic progression-free survival (rPFS), overall survival (OS), and confirmed objective response rate (ORR). An additional efficacy outcome for combined cohorts A and B was rPFS.

The trial demonstrated a statistically significant improvement for olaparib compared to the investigator’s choice in cohort A for rPFS with a median of 7.4 months versus 3.6 months (HR = 0.34; 95% CI = 0.25, 0.47; p < 0.0001), for OS with a median of 19.1 months versus 14.7 months (HR = 0.69; 95% CI = 0.50, 0.97; p = 0.0175), and for ORR of 33% versus 2% (p < 0.0001). The trial also demonstrated a statistically significant improvement for olaparib compared to investigator’s choice for rPFS in cohorts A and B combined, with a median of 5.8 months versus 3.5 months (HR = 0.49; 95% CI = 0.38, 0.63; p < 0.0001).

The most common adverse reactions (≥ 10%) 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 randomized to the olaparib arm compared to 3.1% of those receiving enzalutamide or abiraterone.

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

View full prescribing information for olaparib.

The review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment.

FDA granted olaparib priority review and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.  

For assistance with single-patient oncology investigational new drug applications, contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.