Chemotherapy with or without pembrolizumab followed by maintenance pembrolizumab with or without olaparib as first-line treatment of patients with advanced BRCA non-mutated epithelial ovarian cancer (ENGOT-OV43/GOG-3036/KEYLYNK-001): a randomised, double-blind, placebo-controlled, phase 3 trial

Combination of PD-1 blockade with pembrolizumab and PARP inhibition with maintenance olaparib in patients without a BRCA1/BRCA2 variant, outside the germline-status-based PARP inhibitor indication.

KEYLYNK-001 is a randomised, double-blind phase 3 trial conducted at 224 centres in 22 countries in patients with stage III-IV epithelial ovarian, primary peritoneal or fallopian tube cancer without a BRCA mutation. After one lead-in chemotherapy cycle, 1,367 patients were randomised to pembrolizumab plus chemotherapy followed by pembrolizumab-olaparib maintenance, pembrolizumab plus chemotherapy followed by pembrolizumab-placebo maintenance, or placebo plus chemotherapy. At interim analysis, pembrolizumab-olaparib improved progression-free survival versus control in the CPS ≥ 10 population (HR 0.63; 95% CI 0.49-0.80; p < 0.0001) and in the intention-to-treat population (HR 0.68; 0.58-0.81; p < 0.0001), a benefit maintained at final analysis after 49.6 months median follow-up (HR 0.66 and 0.71). Pembrolizumab alone did not outperform control (HR 0.95; 0.77-1.19; p = 0.33), and grade 3 or higher treatment-related adverse events affected 66% of the pembrolizumab-olaparib group versus 51% of controls.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This trial does not concern germline carriers: that is precisely what makes it relevant to the cancer genetics clinic, since it tests what becomes of the PARP inhibitor once the determinant underpinning its indication is removed. The intention-to-treat HR of 0.71, set against the magnitudes observed in BRCA variant carriers, shows that germline status remains the best discriminator of benefit, and that a statistically significant result in non-mutated patients does not remove the case for testing. The cost is visible: 66% grade 3 or higher events versus 51% with chemotherapy alone, in a population where the absolute gain is more modest — the benefit-risk balance does not transfer from one status to the other.

Analysis by Dr Thibaut Benquey