PARP Inhibitors Still Work in HRD-Low Ovarian Cancer

Homologous recombination deficiency (HRD) scoring failed to predict PARP inhibitor response in BRCA wild-type ovarian cancer, as women with low scores still appeared to derive benefit, an exploratory analysis of a phase III trial showed.

Among 221 patients in the HRD subgroup of VELIA, median progression-free survival (PFS) was 23 months when the investigational PARP inhibitor veliparib was added to carboplatin plus paclitaxel, as compared to 20 months with chemotherapy alone (HR 0.76, 95% CI 0.53-1.09), reported Elizabeth Swisher, MD, of the University of Washington in Seattle.

In the non-HRD subgroup (patients with a Myriad genomic instability score <33), median PFS was 15 months with the combination versus 12.3 months with chemotherapy alone (HR 0.76, 95% CI 0.56-1.03), according to the findings presented at the Society of Gynecologic Oncology (SGO) annual meeting webinar series.

Pointing to the identical hazard ratios, Swisher said both groups received the same degree of benefit with the addition of veliparib, and that the absolute PFS difference between the two groups “suggest that the genomic instability score did not predict benefit of adding veliparib, but does function as a strong prognostic marker.”

Sensitivity analyses using a cutoff of 42, which was used to determine HRD status in other maintenance PARP inhibitor trials for ovarian cancer, yielded the same results.

“Evidence of veliparib benefit can be observed even at very low HRD scores,” said Swisher. “There was no clear cutoff for genomic instability that separates those BRCA wild-type patients who get benefit from the addition of extended veliparib from those who do not.”

VELIA’s main efficacy results, which have been previously reported, showed that patients who received six cycles of 150-mg veliparib plus carboplatin and paclitaxel followed by 400-mg veliparib maintenance had significantly longer PFS compared to those who received chemotherapy alone followed by placebo.

In the intent-to-treat population, median PFS was 23.5 months in the veliparib arm versus 17.3 months for the placebo arm (HR 0.68, 95% CI 0.56-0.83).

“Patients with BRCA-mutated ovarian cancer had the best outcomes,” Swisher said, with a median PFS of 34.7 months with veliparib, as compared to 22.0 months with placebo (HR 0.44, 95% CI 0.28-0.68).

For the current analysis, only BRCA wild-type cases with interpretable genomic instability score results were included, with results stratified by International Federation of Gynecology and Obstetrics stage and residual disease status.

“Dr. Swisher provided us with some data that I know I was sitting on the edge of my chair to find out,” said SGO Distillant Rebecca Arend, MD, of the University of Alabama at Birmingham.

As platinum sensitivity has been considered a surrogate biomarker for HRD, she said, testing for genomic instability prior to first-line treatment was thought to be even more critical when starting PARP inhibitors upfront.

“Guess what? This was not the case,” Arend said.

Contrary to VELIA, she noted, HRD status correlated with the degree of benefit from PARP inhibitor maintenance in the PRIMA trial. And even the non-HRD group had derived benefit, hence the recent FDA approval of niraparib (Zejula) as maintenance therapy following complete or partial response to first-line platinum-based chemotherapy, regardless of HRD status.

Indeed, subgroup data of BRCA wild-type patients in PRIMA, also presented at SGO, showed an improvement with niraparib in both the HRD (HR 0.50, 95% CI 0.31-0.83) and non-HRD subgroups (HR 0.68, 95% CI 0.49-0.94).