In a phase II study, researchers found that the PARP inhibitor olaparib led to stable disease or tumor regressions in patients with advanced breast, ovarian, pancreatic, and prostate cancers who had germline mutations in BRCA1 or BRCA2.
The PARP inhibitor olaparib has already shown promise in treating patients with ovarian and breast cancers who have BRCA1 or BRCA2 germline mutations. Now, a study reported last month in the Journal of Clinical Oncology has found that the drug also shrinks prostate and pancreatic tumors in people who have these mutations.
BRCA mutations disable DNA damage repair via homologous recombination. PARP inhibitors knock out a second repair mechanism called base excision repair. The loss of both can kill tumor cells.
Although no PARP inhibitor is approved for use in the United States, olaparib (Lynparza; AstraZeneca) has been recommended for approval in Europe for advanced ovarian cancer. Researchers are, however, still trying to determine whether patients with other BRCA-associated cancers might respond to the drug. Few studies have measured olaparib's effects in patients with BRCA mutations and prostate or pancreatic cancer, or in patients with BRCA mutations whose ovarian or breast tumors resist first-line treatments.
Susan Domchek, MD, of the University of Pennsylvania in Philadelphia, and colleagues tested olaparib in 298 patients who carried germline BRCA mutations and had already received an average of four prior drug regimens. Most of the patients in this phase II trial had ovarian, breast, prostate, or pancreatic cancers.
The researchers reported that olaparib was effective against all four tumor types:
Of the 62 patients with breast cancer, 12.9% experienced tumor regression and 46.8% had stable disease for at least 8 weeks. Median overall survival (OS) was 11 months.
Of the 193 patients with ovarian cancer, 31.1% experienced tumor regression and 40.4% had stable disease. Median OS was 16.6 months.
Of the 23 patients with pancreatic cancer, 21.7% experienced tumor regression and 34.8% had stable disease. Median OS was 9.8 months.
Of the 8 patients with prostate cancer, 50% experienced tumor regression and 25% had stable disease. Median OS was 18.4 months.
The drug worked equally well whether patients had a mutation in BRCA1 or BRCA2.
The drug triggered side effects such as nausea, fatigue, and anemia. In addition, two patients who had received a significant amount of chemotherapy prior to taking olaparib developed leukemia, Domchek notes.
“The clinical benefit looks quite substantial,” Domchek says. In particular, the result in pancreatic cancer patients “is quite exciting and makes a compelling case to examine additional patients to see if we get the same benefit in a larger trial.”
“That a single targeted drug works in pancreas cancer is striking,” says Eileen O'Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who wasn't connected to the study.
Jonathan Brody, PhD, of Thomas Jefferson University in Philadelphia, PA, agrees. “I think this is an exciting launching-point study,” he says.
Phase III trials of olaparib in breast and ovarian cancer patients with BRCA mutations are already under way, and a phase III trial in patients with pancreatic cancer is about to start. O'Reilly and Brody agree that additional studies should examine whether olaparib works in patients who carry other mutations that disable homologous recombination, such as mutations in the Fanconi anemia genes.