PARP Inhibitor Olaparib Produces High Response Rate in Metastatic Prostate Cancer With DNA Repair Defects
In a phase II trial reported in The New England Journal of Medicine, Mateo et al found that the PARP inhibitor olaparib (Lynparza) produced a high response rate in patients with previously treated metastatic castration-resistant prostate cancer with tumors exhibiting defects in DNA repair genes.
Study Details
In the trial, 50 patients were treated with olaparib at 400 mg twice daily. All patients had received prior treatment with docetaxel, 98% with abiraterone (Zytiga) or enzalutamide (Xtandi), and 58% with cabazitaxel.
The primary endpoint was response rate, defined as objective response, reduction in prostate-specific antigen level of ≥ 50%, or confirmed reduction in circulating tumor cell count from ≥ 5 per 7.5 mL of blood to <5/7.5 mL. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase chain reaction testing were performed on tumor biopsies from all patients.
Response Rates
Overall, response was observed in 16 of 49 evaluable patients (response rate = 33%, 95% confidence interval = 20%–48%). Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes, including BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2, in 16 (335) of the 49. Of these, 14 (88%, P < .001 vs patients negative for biomarkers) had a response to olaparib, including each of seven patients with BRCA2 loss (four with biallelic somatic loss, three with germline mutations) and four of five with ATM aberrations.
Median radiologic progression-free survival was 9.8 months in biomarker-positive patients vs 2.7 months in biomarker-negative patients (P < .001). Median overall survival was 13.8 vs 7.5 months (P = .05).
The most common grade 3 or 4 adverse events were anemia (20%) and fatigue (12%).
The investigators concluded: “Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA repair genes led to a high response rate.”
Johann de Bono, MB, ChB, PhD, of the Institute of Cancer Research is the corresponding author for the New England Journal of Medicine article.
The study was supported by Cancer Research UK, AstraZeneca, and others. For full disclosures of the study authors, visit www.nejm.org.
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