Decisions, decisions, decisions.

Top Line: PARP inhibitors have an established role in advanced ovarian cancer.

The Studies:  However, the only current indication in the front-line setting is for maintenance olaparib for women with BRCA mutations. Three landmark PARP inhibitor trials were presented at ESMO 2019: PAOLA-1 (olaparib), PRIMA (niraparib), and VELIA (veliparib). Here’s the big question each addressed (with some small twists): does maintenance PARP inhibition after platinum-based chemotherapy improve progression free survival in a general population of patients with advanced (stage III and IV) ovarian cancer? But here’s the question that was really being asked: does the benefit of PARP inhibition in BRCA-mutated tumors translate to those with homologous recombination repair deficiency (HRD) and does the size of that subset provide a large enough benefit to get FDA approval for all advanced ovarian cancer (minus BRCA or HRD)? The HRD part has to do with the fact that defects in this DNA repair pathway give tumors a phenotypic BRCA-ness. That means the tumors act--and respond--much like BRCA-mutated tumors. How is HRD determined?  With the myChoice HRD assay. Over half of the patients in these trials had HRD. In PAOLA-1, maintenance bevacizumab was given with or without olaparib following chemo + bev. In PRIMA, maintenance niraparib or placebo was given after chemo alone. In VELIA, patients were randomized to either chemo, chemo + veliparib without maintenance, or chemo + veliparib with veliparib maintenance. In all three trials, the incorporation of a PARP inhibitor significantly improved the primary endpoint of progression-free survival for the entire patient cohort. The subset of patients with HRD in each trial also had a significant improvement in PFS. Here’s where things get tricky. Olaparib didn’t seem to benefit the patients who didn’t have HRD in PAOLA-1. Veliparib concurrent with chemo (but without maintenance) didn’t improve PFS for anyone. Veliparib combo and maintenance also didn’t seem to benefit patients who were HR proficient. It was niraparib, though, that actually seemed to benefit even the HR proficient subset. 

TBL(s): [1] Maintenance niraparib following platinum-based chemotherapy improves PFS among all subsets of patients with advanced ovarian cancer. [2] Veliparib given with chemo and then in maintenance improves PFS for advanced ovarian cancer mainly by benefiting those with HRD. [3] Maintenance olaparib, when added to a bevacizumab containing regimen, improves PFS for advanced ovarian cancer mainly by benefiting those with HRD. | PRIMA and VELIA, N Engl J Med 2019