Niraparib showed promising signs of efficacy in the phase II GALAHAD trial of men with advanced prostate cancer whose tumors harbor mutations in the DNA damage–response pathway, especially among patients with gene defects in BRCA1 or BRCA2.
The case for treating men with advanced prostate cancer whose tumors harbor mutations in the DNA damage–response (DDR) pathway with a PARP inhibitor is strengthening, with the once-daily pill niraparib (Zejula; GlaxoSmithKline) showing signs of efficacy, particularly against cancers with defects in BRCA1 or BRCA2.
At the 2019 Genitourinary Cancers Symposium in San Francisco, CA, in February, researchers reported preliminary findings from the ongoing phase II GALAHAD study—an open-label trial evaluating niraparib in patients with metastatic castration-resistant prostate cancer whose disease progressed following treatment with androgen receptor–targeted therapy and taxane-based chemotherapy.
The study sponsor, Janssen Biotech, which holds the exclusive license for niraparib in prostate cancer, recruited 120 patients who tested positive on a blood test for a DDR mutation in at least one of eight genes. The presentation focused on only those 50 individuals with DDR defects in both copies of any particular gene—so-called biallelic mutation carriers who showed the highest response rates.
Among the 29 patients with BRCA1 or BRCA2 mutations, the response rate, as measured by standard radiologic criteria, was 38%. However, when patients with reduced circulating tumor-cell counts or at least a 50% decrease in prostate-specific antigen were also counted as responders—a composite endpoint—the rate jumped to 62%. Niraparib offered less benefit to the 21 patients with biallelic mutations in ATM, FANCA, PALB2, CHEK2, BRIP1, or HDAC2—yielding response rates of 13% and 24% on the two outcome measures, respectively.
“There's clearly a population of patients with metastatic prostate cancer who respond to PARP inhibitors,” says William Dahut, MD, clinical director of the NCI's Center for Cancer Research in Bethesda, MD, who was not involved in the study. However, “it may not be that all mutations are created equal.”
Approximately half of the 23 patients considered composite responders in the GALAHAD trial took niraparib for 6 months or longer without disease progression—a promising sign given that the median progression-free survival among patients with DNA-repair pathway defects is only about 3 months with approved therapies, notes Margaret Yu, MD, head of prostate clinical development at Janssen.
However, Johann de Bono, MB ChB, PhD, head of the Prostate Cancer Targeted Therapy Group at the Institute of Cancer Research in London, UK, views the data as “extremely disappointing” because GALAHAD merely validated previously published data with the rival PARP inhibitors olaparib (Lynparza; AstraZeneca) and rucaparib (Rubraca; Clovis Oncology).
If anything, the results suggest niraparib may not work as well as other PARP blockers. With the usual caveats about cross-trial comparisons, the composite response rate observed with niraparib was lower than what de Bono's team reported 4 years ago in a trial of twice-daily olaparib treatment in a similar patient population. The objective response rate among biallelic mutation carriers in GALAHAD was also comparable to that reported last year in the phase II TRITON2 study, which included patients with monoallelic DDR defects treated twice daily with rucaparib.
De Bono additionally worries about the accuracy of the circulating tumor cell DNA assay used by the GALAHAD investigators to gauge whether mutations are biallelic or not. “Blood-based testing needs much further optimization for copy-number analyses,” he says. In his trials, de Bono relies on DNA sequencing of biopsied tumor tissue. –Elie Dolgin