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Olaparib Approved: HRR-Mutated Metastatic Castration-Resistant Prostate Cancer

Prostate cancer cells.

The FDA has approved olaparib (LynparzaTM, AstraZeneca Pharmaceuticals LP) for adult patients with homologous recombination repair (HRR)–mutated metastatic castration-resistant prostate cancer (CRPC) who experience disease progression after treatment with enzalutamide or abiraterone acetate. In addition, the FDA approved two companion diagnostic devices: FoundationOne® CDx (Foundation Medicine, Inc.), for the identification of HRR gene alterations, and BRACAnalysis CDx®(Myriad Genetics, Inc.), for the identification of germline BRCA1 and BRCA2 gene alterations.

The approval was based on PROfound (NCT02987543), a phase 3 trial which enrolled 387 patients with HRR-mutated metastatic CRPC whose disease had progressed following treatment with enzalutamide or abiraterone acetate. Eligible patients had prior bilateral orchiectomy or concurrently received a gonadotropin releasing hormone (GnRH) analog. The trial consisted of two cohorts based on HRR mutation status: 245 patients with at least one BRCA1, BRCA2, or ATM gene mutation were assigned to Cohort A, and 142 patients with alterations in any of 12 other HRR genes were assigned to Cohort B.

Patients were randomized in a 2:1 ratio to receive olaparib 300 mg twice daily or investigator's choice of a hormonal agent, either enzalutamide or abiraterone acetate. The primary end point was radiological progression-free survival, with secondary end points of confirmed objective response rate and overall survival.

In Cohort A, olaparib significantly increased median radiological progression-free survival (7.4 vs 3.6 months), median overall survival (19.1 vs 14.7 months), and confirmed objective response rate (33% vs 2%) compared with enzalutamide or abiraterone acetate. In the overall study population, olaparib increased median progression-free survival (5.8 vs 3.5 months). Of the patients in the control group who experienced disease progression, 81% crossed over to receive olaparib.

Adverse events occurring in at least 10% of patients receiving olaparib included anemia (46%), nausea (41%), fatigue/asthenia (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), constipation (18%), back pain (14%), peripheral edema (12%), cough (11%), dyspnea (10%), arthralgia (9%), and urinary tract infection (7%). Grade 3/4 adverse events were experienced by 51% of patients receiving olaparib and 38% of patients in the control group. Venous thromboembolic events, including pulmonary embolism, occurred in a higher proportion of patients receiving olaparib compared with enzalutamide or abiraterone acetate (7.0% vs 3.1%).

"In men with metastatic CRPC who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in HRR, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalutamide or abiraterone," conclude the investigators of PROfound, led by first author Johann de Bono, MD, PhD, Head of the Division of Clinical Studies at the Institute of Cancer Research in London, England, in their publication in the New England Journal of Medicine.

The recommended dose of olaparib for patients with HRR-mutated metastatic CRPC is 300 mg administered orally twice daily, with or without food.

For More Information

de Bono J, Mateo J, Fizazi K, et al (2020). Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. [Epub ahead of print] DOI:10.1056/NEJMoa1911440 (2020). Study of olaparib (LynparzaTM) versus enzalutamide or abiraterone acetate in men with metastatic castration-resistant prostate cancer (PROfound study). NLM identifier: NCT02987543.

LynparzaTM (olaparib) prescribing information (2020). AstraZeneca Pharmaceuticals LP. Available at:

US Food & Drug Administration (2020). FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. Available at:

Image credit: National Institutes of Health

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