Platinum-resistant ovarian cancer (PROC) remains one of the most treatment-refractory malignancies, with a median overall survival (OS) of less than 12 months. Despite initial response to front-line platinum-taxane-based regimens, ovarian cancer (OC) is challenged by limited treatment options, as patients experience eventual recurrence and resistance to mainstay treatments. Immunotherapy has been explored as a potential strategy in OC. However, single-agent checkpoint inhibitors such as MSD’s Keytruda (pembrolizumab) and Bristol Myers Squibb and Ono Pharmaceutical’s Opdivo (nivolumab) have yet to deliver a major impact in OC, in contrast to their established benefit in endometrial and cervical cancers. The Phase III ENGOT-ov65/KEYNOTE-B96 study, presented at the European Society for Medical Oncology (ESMO) 2025 Congress, held October 17–21, represents a significant effort to redefine the therapeutic potential of immune checkpoint inhibition in PROC.
The study evaluated Keytruda versus placebo, each in combination with weekly paclitaxel with or without Roche’s Avastin (bevacizumab), in PROC patients who have received one or two prior lines of systemic therapy, including at least one prior platinum-based therapy. In a notable development, Dr. Nicoletta Colombo of the European Institute of Oncology (IEO) in Milan announced that the FDA has granted priority review for Keytruda based on these data, underscoring the clinical significance of these results.
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The trial met its primary endpoint of progression-free survival (PFS) in both PD-L1-expressing and all-comer populations. At the first interim analysis (median follow-up of 15.6 months), Keytruda demonstrated a significant improvement in PFS both in patients with PD-L1 CPS ≥1 (8.3 vs 7.2 months; HR 0.72 [95% CI, 0.58–0.89]; P=0.0014) and in the overall study population (8.3 vs 6.4 months; HR 0.70 [95% CI, 0.58–0.84]; P<0.0001). At the second interim analysis (median follow-up of 26.6 months), overall survival (OS) was significantly prolonged in the PD-L1 CPS ≥1 subgroup (18.2 vs 14.0 months; HR 0.76 [95% CI, 0.61–0.94]; P=0.0053), with a favourable trend also observed in the overall population (17.7 vs 14.0 months; HR 0.81 [95% CI, 0.68–0.97]; P=0.0114). Safety findings were consistent with the known profiles of Keytruda and paclitaxel, and no new immune-related toxicities were observed.
The control arm of weekly paclitaxel and optional Avastin reflects real-world practice established by the AURELIA study. However, this introduces heterogeneity that may complicate interpretation, as Avastin confers a modest PFS benefit and variable OS impact. While the double-blind design enhances the rigour of the study, questions remain over the magnitude of benefit and the potential influence of Avastin use between arms. Nevertheless, this appears to be a potential limitation, but not a significant one, as enthusiasm around these results was palpable at ESMO. The data is clinically meaningful and practice-relevant as Keytruda is the first checkpoint inhibitor to generate a survival benefit in PROC.
As noted in GlobalData’s Ovarian Cancer: Opportunity Assessment and Forecast report, key opinion leaders (KOLs) have historically regarded OC as relatively unresponsive to checkpoint blockade. This is reflected in KEYNOTE-100, where Keytruda monotherapy achieved only an 8% objective response rate, far lower than its performance in microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) endometrial cancer. However, KOLs did note that with potential approval, Keytruda would generate excitement in clinical practice as a valuable addition to combination regimens including chemotherapy, poly ADP-ribose polymerase (PARP) inhibitors, and angiogenesis inhibitors.
According to GlobalData’s analyst consensus forecast, Keytruda is projected to reach global annual sales of $19bn by 2031 supported by its continued expansion into new tumour types. A label expansion for Keytruda in PROC would further entrench MSD’s dominance in the PD-1 space and broaden its immuno-oncology portfolio in gynaecological malignancies. Although competition will persist with established antibody-drug conjugates (ADCs) such as ImmunoGen’s Elahere (mirvetuximab soravtansine) for folate receptor-alpha (FRα)-high disease and emerging ADCs like AstraZeneca and Daiichi Sankyo’s Dato-DXd (datopotamab deruxtecan), Keytruda’s combination strategy offers an alternative for PD-L1-positive, FRα-low PROC patients, particularly in markets with limited ADC access. While longer OS follow-up and biomarker refinement will determine the ultimate impact on practice, the ENGOT-ov65/KEYNOTE-B96 study represents an impressive and unexpected success for immunotherapy in PROC. Despite prior scepticism, Keytruda’s demonstrated efficacy and safety, and the FDA priority review signal a meaningful advancement toward a new treatment paradigm for patients with PROC.
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