Daily oral olaparib induced a 33% response rate in refractory, progressing prostate cancer in an international phase II clinical trial. The study was published online Oct. 29 in the New England Journal of Medicine.
Researchers hypothesized that olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor recently approved for treatment of ovarian cancers with BRCA1/2 mutations, would also show antitumor activity in sporadic cases of metastatic, castration-resistant prostate cancer in which the tumors expressed DNA-repair defects. During a 2-year period, the researchers identified 49 patients at seven medical centers to participate in the study.
©2015 AACR/Todd Buchanan
Dr. Joaquin Mateo
Fresh biopsy samples, obtained before treatment began, were used for germline whole-exome sequencing and transcriptome studies, said Dr. Joaquin Mateo of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, both in London, and his associates.
Participants took 400-mg tablets of olaparib twice daily until they showed radiologic progression, unequivocal clinical progression, or unacceptable side effects, or until they died. After a median follow-up of 14.4 months (range, 1.4-21.9 months), median overall survival was 10.1 months. Twelve patients survived more than 6 months on olaparib, and four survived more than 12 months on the drug.
The primary end point – treatment response rate – was 33%, with 16 of the 49 patients demonstrating a radiologic response on CT scanning, regression of bone metastases on serial MRI scanning, a reduction of 50% or more in PSA level, and/or “impressive” reductions in the number of circulating tumor cells to less than 5 per 7.5 mL (N Engl J Med. 2015 Oct 29. doi:10.1056/NEJMoa1506859).
Genetic testing of the tumor samples showed that 16 patients had tumor aberrations in DNA-repair genes, including BRCA2, ATM, BRCA1, PALB2, CHEK2, FANCA, and HDAC2. Fourteen of these 16 patients responded to olaparib. In contrast, 2 of the 33 patients whose tumors did not have aberrations in DNA-repair genes responded to olaparib. In addition, radiologic progression-free survival was significantly longer in the group with mutations in the DNA-repair genes (median, 9.8 months) than in the other group (2.7 months). Overall survival also was significantly longer (median 13.8 months vs. 7.5 months).
Three patients permanently discontinued olaparib because of adverse events, chiefly anemia. Another 13 patients required dose reductions. Drug-related toxicity included anemia (affecting 20% of patients), fatigue (12%), leukopenia (6%), thrombocytopenia (4%), and neutropenia (4%).
Prostate cancers characterized by defects in DNA repair are thought to comprise 25%-30% of all sporadic, castration-resistant prostate cancers. These study findings suggest that this commonly occurring subset of tumors can be molecularly stratified for treatment. Their results demonstrate that identifying predictive biomarkers from fresh tumor-biopsy samples is feasible, and that “next-generation sequencing analyses of tumor-biopsy samples can increase our understanding of treatment responses,” Dr. Mateo and his associates said.
They added that the DNA-repair defects found in these tumors may prove sensitive to platinum-based chemotherapies. This type of treatment usually is not used for metastatic, castration-resistant prostate cancer because phase III studies haven’t shown a survival benefit in unselected patients. However, anecdotal responses to platinum analogues have been reported, and emerging data show that PAPR-inhibitors show antitumor activity against similar (ovarian) cancers.
Cancer Research U.K., Royal Marsden NHS Foundation Trust, Stand Up To Cancer–Prostate Cancer Foundation, Prostate Cancer U.K., National Institute for Health Research, Medical Research Council–Prostate Cancer U.K., Swiss Cancer League, Marie Curie International Incoming Fellowship, and the Investigator-Sponsored Study Collaboration between AstraZeneca and the National Institute for Health Research Cancer Research Network funded the study. AstraZeneca provided the olaparib used in the trial. Dr. Mateo reported having no disclosures; his associates reported ties to numerous industry sources.