Abstract
Data from the phase II TOPARP-A clinical trial indicate that men with metastatic castration-resistant prostate cancer are more likely to respond to the PARP inhibitor olaparib if they have mutations in DNA damage repair genes. The study provides the first data supporting molecular stratification for patients with this disease.
Results from the phase II TOPARP-A clinical trial show durable antitumor activity with the PARP inhibitor olaparib (Lynparza; AstraZeneca) among a subset of patients with metastatic castration-resistant prostate cancer (CRPC). These men all had genetic aberrations in various DNA damage repair genes, notably BRCA2 and ATM.
Joaquin Mateo, MD, explains the findings of a phase II trial of the PARP inhibitor olaparib in patients with metastatic castration-resistant prostate cancer.
Joaquin Mateo, MD, explains the findings of a phase II trial of the PARP inhibitor olaparib in patients with metastatic castration-resistant prostate cancer.
The trial data were reported by Joaquin Mateo, MD, a medical oncologist at The Institute of Cancer Research in the United Kingdom, at the American Association for Cancer Research Annual Meeting 2015 in Philadelphia, PA, April 18–22.
Olaparib operates on the concept of synthetic lethality: Cancer cells lacking BRCA1 or BRCA2 depend instead on PARP-regulated DNA repair, and are hypersensitive to PARP suppression.
“Preclinical models of prostate cancer have shown that mutations in other DNA damage repair genes also induce sensitivity to PARP inhibition,” Mateo said. “This study was about proving that if you have aberrations in any of these genes, not just BRCA, the effect is the same—a good response to olaparib. It's provided the first data supporting molecular stratification for prostate cancer patients.”
TOPARP-A enrolled 50 patients with advanced CRPC, none having received PARP inhibitor therapy, but all having previously been given drugs such as the CYP-17 inhibitor abiraterone (Zytiga; Janssen Biotech), the androgen receptor antagonist enzalutamide (Xtandi; Medivation), and taxane chemotherapy. Sixteen of 49 evaluable patients responded to olaparib—four for over a year, which Mateo considered “quite a big achievement for a late-stage cancer population.” Five study patients are still being treated with olaparib.
Next-generation sequencing of tumor samples from the 16 responders revealed defects across a panel of DNA damage repair genes, including FANCA, CHEK2, PALB2, and HDAC2. Mutations in BRCA2 and ATM were the most common. Interestingly, three of five patients with ATM defects had germline mutations, “something not well described in prostate cancer before,” Mateo said. He also noted that the two patients with PALB2 and HDAC2 aberrations, respectively, represented the first proof of preclinical observations that both of these loss-of-function mutations sensitize tumor cells to olaparib.
The main side effects seen with olaparib were anemia and fatigue; overall, the drug was much better tolerated by these patients, with none of the gastrointestinal effects observed in ovarian cancer studies.
Mateo and his group are currently enrolling patients who have the relevant DNA damage repair gene mutations in TOPARP-B, the second stage of this trial, hoping to validate their initial findings.
“We've gotten good mileage out of androgen receptor–targeting drugs, and my prediction is that we'll see more drug development around new targets in coming years,” said William Nelson, MD, PhD, director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, MD, who moderated the press conference at which the results were presented.
“I think we'll also see more studies trying to identify other molecularly distinct subsets of prostate cancer patients, and attempts to develop drugs for these groups,” Mateo added.
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