ESMO: GSK's Zejula misses survival goal in first-line ovarian cancer, combo disappoints

The PARP inhibitor class, which includes drugs from GSK, AstraZeneca/Merck, and pharma&, has faced significant regulatory challenges before the recent clinical setbacks. In a challenging day for PARP inhibitors in ovarian cancer, GSK’s Zejula failed to show a life extension benefit in the final analysis of its phase 3 trial, and pharma&'s attempt to enhance Rubraca with Bristol Myers Squibb’s Opdivo backfired.

GSK’s Zejula holds broad U.S. approval as a first-line maintenance treatment for ovarian cancer patients who have responded to initial platinum-based chemotherapy. However, the phase 3 PRIMA study that earned Zejula this approval recently revealed at the European Society for Medical Oncology (ESMO) 2024 annual meeting that the drug did not extend patients' lives compared to placebo. After approximately 74 months of median follow-up, patients taking Zejula lived a median of 46.6 months, compared to 48.8 months for placebo, indicating a 1% higher risk of death for those on Zejula.

This marginally negative overall survival outcome raises the possibility of an FDA crackdown similar to the one two years ago, which led to the withdrawal or restriction of several later-line ovarian cancer indications for Zejula, AstraZeneca and Merck’s Lynparza, and the then-Clovis Oncology-owned Rubraca due to potential long-term survival detriments.

GSK’s head of oncology R&D, Hesham Abdullah, M.D., noted that Zejula’s risk of death in the PRIMA trial turned negative only after including a small group of patients with undetermined status on the homologous-recombination biomarker. Zejula showed a 5% reduction in the risk of death for homologous recombination-deficient (HRd) tumors and a 7% improvement for homologous recombination-proficient (HRp) tumors, though these figures were not statistically significant.

Despite this, Zejula secured FDA approval in 2020 for first-line maintenance treatment of ovarian cancer regardless of biomarker status, based on PRIMA data showing a 38% reduction in the risk of disease progression or death versus placebo. The greatest benefit was observed in patients with BRCA mutations, followed by other HRd types and HRp tumors.

Abdullah mentioned that subsequent therapies likely confounded the overall survival analysis, as 38% of placebo patients received subsequent PARP inhibitor treatment compared to 12% for Zejula patients. This disparity was even more pronounced in the HRd subgroup, with 48% of placebo patients receiving subsequent treatment versus 16% for Zejula patients.

Despite these challenges, Zejula continued to show benefits in slowing disease progression or death, with 22% of Zejula patients estimated to be alive at five years, compared to 12% for placebo. In the HRd population, these rates were 35% and 16%, respectively. Abdullah expressed confidence in the long-term safety profile and data supporting Zejula's use despite the impact of subsequent therapies.

On the other hand, pharma&'s Rubraca faced setbacks with its combination therapy approach. The Austrian company previously acquired Rubraca from the bankrupt Clovis Oncology and had combined it with Bristol Myers Squibb’s Opdivo, but this combination failed in clinical trials. Data from the phase 3 ATHENA-COMBO trial presented at ESMO 2024 showed that patients treated with the Rubraca-Opdivo combination had worse outcomes than those treated with Rubraca alone. The combo resulted in a 30% increased risk of disease progression or death compared to solo Rubraca.

The ATHENA-COMBO trial was a failure across all patient groups, with the combination showing worse results in terms of progression-free survival (PFS) and higher rates of adverse events. Despite the negative results, a pharma& spokesperson suggested that the findings support Rubraca monotherapy in the first-line maintenance setting, although Rubraca has not yet received FDA approval for this use. The FDA previously rejected Rubraca’s application for first-line maintenance treatment, requesting long-term overall survival analysis from the phase 3 ATHENA-MONO trial.

While Rubraca’s first-line bid remains blocked by the FDA, the European Commission approved it for this indication last November, and it recently secured reimbursement in France for first-line maintenance use.