The addition of veliparib during chemotherapy and maintenance benefits women with high-grade serous ovarian cancer without BRCA mutations independent of homologous recombination deficiency (HRD) status, according to an analysis of the VELIA/GOG-3005 trial.

Recently, four seminal phase III clinical trials explored the role of PARP inhibitors in the treatment of ovarian cancer in a largely unselected population: VELIA, PAOLA-1, PRIMA, and SOLO-1. VELIA was unique among these studies in that PARP inhibitor therapy was delivered in combination with initial chemotherapy, and that maintenance PARP therapy was delivered to all patients randomized to that treatment arm. In the other studies, PARP inhibitors were only used as maintenance therapy, and patients were only eligible for this maintenance therapy if they exhibited a response to initial chemotherapy.

The next step was to determine which biomarkers can help identify patients most likely to benefit from a PARP inhibitor and, more importantly, which patients are so unlikely to benefit that the risks of using this approach outweigh the benefits. One such analysis of the VELIA trial explored the utility of HRD status as a biomarker. The findings were slated to be presented at the Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, scheduled to take place March 28 to 30, 2020 in Toronto, Canada. The meeting was cancelled due to the COVID-19 pandemic, but the study abstracts were released online.

“We are looking for predictors for who to best utilize these treatments in,” lead author of this analysis of the VELIA findings, Elizabeth M. Swisher, MD, from the University of Washington Medical Center in Seattle, told BreakingMED. “If we can identify predictors of patients who get more benefit, that is important to be able to counsel patients. We know that the BRCA mutations are an important predictor, and the way we counsel our patients is different than patients without mutations… If we have predictors that apply to patients who do not have BRCA mutations in their cancers, then we can have similar type of conversations with those patients.”

In the original intention-to-treat analysis of VELIA, progression-free survival (PFS) hazard ratio (HR) was 0.80 (95% CI 0.56-0.83; P < .001) when comparing those who received veliparib throughout the chemotherapy and maintenance phase with those who received placebo.

In this analysis of 532 patients with no BRCA mutations, the HRD-positive population had a PFS HR of 0.77 (95% CI 0.54-1.10) favoring use of veliparib. In the HRD-negative population, the PFS HR was similar, at 0.76 (95% CI 0.55-1.03). In both cases, the upper confidence intervals crossed the threshold of 1.00 in this post-hoc analysis.

When the investigators compared HRD score versus observed HR between the veliparib-throughout and control-throughout groups, no clear HRD cutoff score could be identified to accurately determine who would benefit most from the veliparib-throughout regimen. Even patients with very low HRD scores benefited from the addition of veliparib.

That is good news and bad news, depending on how you look at it, said Swisher. “It’s a bad thing if you’re not finding more benefit in a specific subgroup,” she noted, “but it’s also a good thing to show that you actually are getting benefit across the whole population, which has not always been the case.”

For the VELIA study, 1,140 patients with untreated stage III to IV high-grade serous ovarian carcinoma received 6 cycles of carboplatin and paclitaxel on a 21-day interval following primary cytoreduction or as neoadjuvant chemotherapy, with interval cytoreduction. These patients were randomized to one of three treatment groups: Group 1 (n = 382) received veliparib 150 mg twice daily in combination with chemotherapy as well as maintenance veliparib 400 mg twice daily for cycles 7 to 36; Group 2 (n = 383) received veliparib 150 twice daily in combination with chemotherapy, followed by a placebo during the maintenance phase; Group 3 (n = 375) received placebo during both the chemotherapy and maintenance phases. Randomization was stratified by disease stage, timing of surgery, residual disease post-primary surgery, paclitaxel schedule, geographic region, and germline BRCA status, but not HRD.

This analysis of response by HRD status among 532 patients was restricted to those randomized to Groups 1 and 3 who had no BRCA mutations. These patients were classified as HRD-negative if they had an HRD score < 33 and HRD-positive if they had an HRD score ≥ 33.

“Our study shows that, in the setting where we are combining the PARP inhibitor with the chemotherapy, and none of the other studies [examining the role of PARP inhibitors in ovarian cancer] do that, there seems to be a benefit even for the non-HRD population that’s equivalent to the HRD population,” said Swisher. “What we would speculate is that the combination of the PARP inhibitor with chemotherapy may be potentiating the impact of chemotherapy. It may be operating in a little bit of a different way than just purely as a PARP inhibitor as maintenance therapy. So, the reason we might be providing the equivalent benefit to the non-HRD cases may be because of the specific regimen that we are using.”

In a comment on the study for BreakingMED, Kathleen Moore, MD, of the Stephenson Cancer Center at the University of Oklahoma in Oklahoma City, said the findings are important for patient selection, but they do need to be confirmed in prospective studies.

“This analysis is important because it shows that while the assay is helpful… it’s not a discriminatory assay for who should get PARP and who should not,” she said. “This shows the need for further development of a more refined test to identify patients who will not benefit from at all from a PARP.”

She pointed out, however, that HRD status is prognostic. Patients with low HRD scores had poorer outcomes, despite having the same magnitude of benefit from PARP inhibitors as those with high scores. “This is a group of patients we really need to study and figure out… what intervention in addition to PARP or instead of PARP is going to help them have a longer progression-free and hopefully overall survival,” she said.