Abiraterone–Olaparib Combo Aids Men with mCRPC

For patients with metastatic castration-resistant prostate cancer (mCRPC), response to treatment is often short-lived. However, at the 2018 American Society of Clinical Oncology Annual Meeting in Chicago, IL, earlier this month, and in a concurrently published study, researchers reported that combining the antiandrogen abiraterone and the PARP inhibitor olaparib significantly improved progression-free survival (PFS) in these patients compared with abiraterone alone.

Moreover, this treatment extended PFS regardless of whether patients' tumors carried homologous recombination repair (HRR) mutations. Past trials have shown that olaparib improves treatment response in patients with mCRPC who have HRR deficiencies, such as BRCA2 mutations. In these patients, HRR mutations prevent tumor cells from repairing double-strand DNA breaks, while the PARP inhibitor prevents them from repairing single-strand DNA breaks. This double whammy to the DNA-repair system leads to catastrophic damage and tumor cell death.

The current study is different because “we took all comers,” says Fred Saad, MD, of the Institut du Cancer de Montréal in Canada, senior author of the article. “Patients that had no DNA damage–response deficiencies seemed to benefit just as much as patients with BRCA mutations or other DNA damage–response deficiencies.” The study was inspired by preclinical data suggesting that antihormonal drugs such as abiraterone, a standard treatment for advanced prostate cancer, could induce a BRCAness phenotype, making tumors more sensitive to PARP inhibitors.

In Saad's phase II trial of 142 men with mCRPC, median PFS was 13.8 months among patients who received abiraterone plus olaparib versus 8.2 months among patients who received abiraterone plus placebo, a significant difference. HRR mutation status was available for only 56 (39%) of the 142 patients. Of these patients, 21 had HRR mutations and 35 did not. In both groups, the combination treatment increased PFS; however, the study was not powered to detect whether these increases were statistically significant. In addition, any of three assays could have been used to assess HRR status.

Howard Scher, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, says that, though interesting, the results should be interpreted cautiously. In particular, to establish that patients with and without HRR mutations benefit from combination therapy, larger, adequately powered trials using a single validated assay to assess HRR mutation status are necessary. “At present there are no approved diagnostic tests for this use,” he says, though he notes a range of assays are being developed for this purpose.

He says another concern is the higher frequency of grade 3 or worse adverse events in the combination treatment arm compared with abiraterone monotherapy (52% vs. 28%, respectively), which shows that the therapy is not ready for widespread use outside of a clinical trial. “This is particularly the case for patients with more advanced disease, who may be at greater risk for toxicity.”

Saad agrees that these findings must be confirmed before strong conclusions are drawn and says that a phase III trial, currently under development, will allow researchers to learn more about the combination treatment, including the magnitude of its benefit in patients with and without HRR mutations. –Kristin Harper