Platinum Sensitivity, Genomic Markers Associated With Rucaparib Response for High-Grade Ovarian Carcinoma

Part 2 of the phase 2 ARIEL2 trial and a post hoc exploratory biomarker analysis published in Nature Communications determined that certain clinical features and genomic markers were predictive of sensitivity to both platinum and rucaparib (Rubraca) in patients with relapsed high-grade ovarian carcinoma (HGOC).

This study considered data from the international, open-label trial (NCT01891344), which assessed safety and efficacy of the PARP inhibitor (PARPi) as active therapy for patients with relapsed HGOC, with data from part 2 detailed in the research.

“ARIEL2 assessed the safety and efficacy of rucaparib in an unselected HGOC population,” wrote the investigators. “Platinum sensitivity was a strong clinical predictor of rucaparib response in this PARPi-naïve population, especially in the BRCAmut and BRCAwt/LOH-high molecular subgroups.”

A total of 287 patients with HGOC were enrolled in part 2 of the ARIEL2 trial to receive rucaparib. Eligible patients received 3 to 4 prior chemotherapies, including those with platinum-sensitive or platinum-resistant/refractory disease.

Patients with HGOC were separated into 3 homologous recombination deficiency (HRD) groups: BRCA-mutant (BRCAmut), BRCA wild-type (wt)/loss of heterozygosity (LOH)-high, and BRCAwt/LOH-low.

When analyzing the primary end point of confirmed objective response rates (ORR) in part 2, the results showed an ORR of 31.0% (95% CI, 21.3-42.0) for patients with BRCAmut HGOC, 6.8% (95% CI, 2.3-15.3) for patients with BRCAwt/LOH-high HGOC, and 5.6% (95% CI, 2.1-11.8) for patients with BRCAwt/LOH-low HGOC. Durable responses were observed across all HRD subgroups.

Looking at both parts 1 and 2 of the trial, patients sensitive to platinum therapy had a median PFS of 9.4 months with an ORR of 64.9% (95% CI, 52.9-75.6). This was significantly better than patients with platinum-resistant or platinum-refractory disease, who had a median PFS of 7.2 months (HR, 0.44; 95% CI, 0.30-0.63; P < .0001) with an ORR of 23.4% (95% CI, 13.8-35.7; P < .0001).

Of note, alterations in RAD51C and RAD51D and BRCA1 promoter methylation were associated with a positive response to rucaparib and should therefore be considered when testing patients for genomic alterations. RAD51C/D was also strongly associated with response to platinum.

The observed safety profile was consistent with previously reported data investigating rucaparib for this patient population.

“Our analysis highlights significant overlap between molecular mechanisms resulting in platinum and PARPi sensitivity and the extent of cross-resistance that exists between these two drug classes,” wrote the investigators.

The research team suggests that rucaparib should be integrated into earlier lines of therapy for this cohort of patients, specifically for patients with BRCAmut and BRCAwt/LOH-high HGOC and before platinum resistance emerges.

Utilizing this approach should increase the likelihood of a clinical benefit for patients, while maintaining the improved quality of life associated with targeted therapies compared with systemic therapies.

Reference:

Swisher EM, Kwan TT, Oza AM, et al. Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2). Nat Commun. 2021;12(1):2487. doi:10.1038/s41467-021-22582-6