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Olaparib Shows Activity in Prostate Cancer With DRR Mutations

Key clinical point: Olaparib demonstrated antitumor activity in metastatic castration-resistant prostate cancer (mCRPC) with DNA damage response (DDR) gene aberrations.

Major finding: Confirmed composite response was achieved in 54.3% of evaluable patients in the 400-mg cohort and 39.1% of evaluable patients in the 300-mg cohort.

Study details: The data come from an open-label, phase 2 trial of patients with mCRPC with DDR mutations, who were randomly assigned to receive either 400 mg or 300 mg olaparib twice daily in continuous 4-week cycles.

Disclosures: The study was funded by Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres. Most of the authors reported receiving grants and personal fees from multiple pharmaceutical companies, including AstraZeneca.

Commentary

Patients afflicted with metastatic castrate-resistant prostate cancer have few options once prostate cancer no longer responds to taxanes, abiraterone, or enzalutamide. The discovery of increased frequency of DNA-repair enzyme mutations in germline and tumor tissues in patients with prostate cancer has led to studies designed to evaluate the inhibition of poly (ADP-ribose) polymerase (PARP). PARP inhibitors have clinical benefit in other cancers in patients with pre-existing DNA-repair enzyme mutations, such as breast and ovarian cancer. Mateo et al. evaluated whether olaparib at two different dosing levels would have activity in patients whose prostate cancer had progressed on a taxanes. A higher composite response (radiographic or PSA response or decrease in circulating tumor cells) was seen in the cohort receiving the higher dose. This small phase 2 study confirmed activity for olaparib in this patient cohort and provides further support for the ongoing phase III trials designed to evaluate this approach.—Mark Klein, MD

Citation:

Mateo J et al. Lancet Oncol. 2019 Dec 2. doi: 10.1016/S1470-2045(19)30684-9.