FDA Approves Olaparib for Certain Metastatic Prostate Cancers

Nick Mulcahy

May 20, 2020

The US Food and Drug Administration approved olaparib (Lynparza, AstraZeneca) for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).

The drug is limited to use in men who have progressed following prior treatment with enzalutamide or abiraterone.

Olaparib becomes the second PARP inhibitor approved by the FDA for use in prostate cancer this week. Earlier, rucaparib (Rubraca, Clovis Oncology) was approved for use in patients with mCRPC that harbor deleterious BRCA mutations (germline and/or somatic).

Olaparib is also indicated for use in ovarian, breast, and pancreatic cancers.

The FDA also approved two companion diagnostic devices for treatment with olaparib: the FoundationOne CDx test (Foundation Medicine) for the selection of patients carrying HRR gene alterations and the BRACAnalysis CDx test (Myriad Genetic Laboratories) for the selection of patients carrying germline BRCA1/2 alterations.

The approval was based on results from the open-label, multicenter PROfound trial, which randomly assigned 387 patients to olaparib 300 mg twice daily and to investigator's choice of enzalutamide or abiraterone acetate. All patients received a GnRH analog or had prior bilateral orchiectomy.

The study involved two cohorts. Patients with mutations in either BRCA1BRCA2, or ATM were randomly assigned in cohort A (n = 245); patients with mutations among 12 other genes involved in the HRR pathway were randomly assigned in cohort B (n = 142); those with co-mutations were assigned to cohort A.

The major efficacy outcome of the trial was radiological progression-free survival (rPFS) (cohort A).

In cohort A, patients receiving olaparib had a median rPFS of 7.4 months vs 3.6 months among patients receiving investigator's choice (hazard ratio [HR],  0.34; P < .0001). Median overall survival was 19.1 months vs. 14.7 months (HR, 0.69;
P = .0175) and the overall response rate was 33% vs 2% (P < .0001).

In cohort A+B, patients receiving olaparib had a median rPFS of 5.8 months vs 3.5 months among patients receiving investigator's choice (HR, 0.49;
P < .0001).

The study results were first presented at the 2019 annual meeting of the European Society for Medical Oncology. At that time, study investigator Maha Hussain, MD, Northwestern University, Chicago, said the rPFS result and other outcomes were a "remarkable achievement" in such heavily pretreated patients with prostate cancer.

Patients with prostate cancer should now undergo genetic testing of tumor tissue to identify the roughly 30% of patients who can benefit — as is already routinely being done for breast, ovarian, and lung cancer, said experts at ESMO.

The most common adverse reactions 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 olaparib compared with 3.1% of those receiving investigator's choice of enzalutamide or abiraterone.

Olaparib carries the warning that myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) occurred in <1.5% of patients exposed to it as a monotherapy, and that the majority of events had a fatal outcome.

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

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