Post marketing clinical study results of rucaparib in Ovarian Cancer

Heterogeneous nature of ovarian cancer assume significance for diversify causative agents. BRCA oncogene also could be a causative factor for ovarian cancer and ~11% mutation in the BRCA-1 gene, and ~10% mutation in BRCA-2 gene respectively generally occur. Platinum bases chemotherapies are main stream treatment options in initial lines of therapy, Chemo resistance for frontline chemotherapies leading to higher recurrence rate in OC. In advance lines, care givers tend to change different combination regimen which are used in earlier lines. PARP inhibitors are approved in ovarian cancer mostly for maintenance therapy or treatment in fourth or later line of therapy. The efficacy outlook of front-line agents have been poor and care givers feel huge unmet need in relapse or refractory ovarian cancer patients.

In December 2016, the US.FDA approved CLOVIS’ Rubraca as a mono therapy for t advanced ovarian cancer patients with deleterious BRCA mutation after progression on at least 2 Lines of therapy. Rubraca is  a “PARP—a protein that helps repair DNA when it becomes damaged” Inhibitor. It was first and only PARP inhibitor approved for such indication. Approval was granted under the FDA’s accelerated approval program based on clinical study data from Study 10 and ARIEL2.

ARIEL4 post marketing clinical trial have been investigating rucaparib and despite the improved benefit in stalling disease progression, the drug could not provide improvement in overall survival. Rucaparib was found to increase risk of death in treatment arm. Discouraged with the clinical findings the Clovis chose to voluntarily withdraw the approval for rucaparib in the US and European market as well for this patient segment. Analyst’s estimate that such recalls will adversely impact revenue market share of rucaparib in OC and other indications as well. Rucaparib’s withdrawal will certainly be worrisome to both patients and caregivers as it once again leaves a huge void in the treatment paradigm of resistant/refractory ovarian cancer

As updated data from ARIEL4 study failed to impress, the Clovis’s prospect, in sNDA submission for “first-line maintenance” treatment in OC based on ATHENA-MONO trial data, may also face hindrance from regulators. US.FDA has already advised the drug makers, that they should not submit the first-line maintenance sNDA until OS findings from the ATHENA-MONO trial are as much as 50% mature. The FDA’s advice pushes the sNDA submission to a minimum delay of two more years.

It will be interesting to watch the chronology of outcomes especially overall survival in rucaparib arm of ARIEL4 study at ESMO 2022.