In the phase II TOPARP-A clinical trial, patients with metastatic castrate-resistant prostate cancer who were treated with the PARP inhibitor olaparib lived nearly three times longer without their cancer worsening if their tumors had mutations in at least one of 12 DNA repair genes. However, physicians say that a larger trial is needed to confirm olaparib's effectiveness against the disease before they start routinely sequencing tumors and prescribing the drug.
The synthetic lethality that the PARP inhibitor olaparib (Lynparza; AstraZeneca) confers on ovarian tumors with BRCA mutations appears to extend to recurrent metastatic prostate cancers containing several mutated DNA repair genes. If additional clinical trials confirm the drug's efficacy, whole-exome and targeted next-generation sequencing could be used to systematically find mutations and identify patients most likely to respond to olaparib.
The phase II TOPARP-A clinical trial tested olaparib in 49 men with metastatic castration-resistant prostate cancer (CRPC). The 16 men (33%) whose cancers had deletions or deleterious mutations in one or more of 12 DNA repair genes—including BRCA1, BRCA2, and ATM—experienced progression-free survival that was more than three times longer than the 33 men who lacked such mutations. A large-scale sequencing study of mutations in metastatic CRPC detected a smaller, but still sizable, distribution, with 23% of sequenced tumors carrying at least one of the DNA repair gene mutations.
“Since nearly 30,000 patients die of metastatic prostate cancer per year in the U.S., identifying this subset of patients with a clinically actionable mutation in DNA repair pathways could have a significant impact,” says Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor, and one of the study's senior authors. Chinnaiyan was also a senior author on the sequencing study.
Approved in late 2014 for the treatment of ovarian cancer with BRCA germline mutations, olaparib appears to target multiple members of the PARP protein family, but its role in synthetic lethality has been studied most often with PARP1. This protein binds to single-strand DNA breaks to recruit repair proteins, and inhibiting its function blocks single-strand DNA repair. Cells deficient in BRCA1, BRCA2, or ATM cannot repair double-strand DNA breaks, and when single-strand DNA repair is inhibited by olaparib, these cells undergo apoptosis.
In patients with metastatic CRPC, Chinnaiyan and his team have since employed whole-exome sequencing and RNA sequencing to select patients with DNA repair gene mutations for olaparib treatment. Because these patients had already been treated with anti-androgens and other drugs, their tumors may have evolved and developed additional mutations, decreasing the effectiveness of PARP inhibitors. Chinnaiyan thinks that earlier treatment with olaparib, or using it in combination with a second-generation anti-androgen, such as abiraterone (Zytiga; Janssen Biotech) or enzalutamide (Xtandi; Medivation/Astellas), may lead to a more durable response.
Chinnaiyan suggests that “the newer way of thinking is first to understand the molecular or mutational blueprint of a patient's tumor, and then treat accordingly.”
Because PARP inhibitors target DNA replication in actively dividing cells, slowly growing prostate tumors, even if they have BRCA mutations, could be unresponsive to olaparib. Oncologists may thus prefer to stick with the standard of care for now, says Ashley Ross, MD, PhD, a surgeon and professor of urology, oncology, and pathology at Johns Hopkins School of Medicine, Baltimore, MD. Although he and his Hopkins colleagues are excited about the possibility of extending their patients' survival with olaparib, they are not currently prescribing it to treat prostate cancer, an off-label use. Ross says they plan to wait for a phase III clinical trial to demonstrate that olaparib actually improves survival before they begin routinely sequencing tumors to determine who is most likely to respond to the drug.
“The study is an intriguing look at a personalized medicine approach,” says Ross. “The study is particularly important as there are not that many options for men with metastatic castration-resistant prostate cancer who have failed multiple prior treatments.”
- ©2015 American Association for Cancer Research.