First Survival Improvement With Immunotherapy in Platinum-Resistant Ovarian Cancer: Pembrolizumab

For many years, platinum-resistant ovarian cancer has remained one of oncology's most challenging areas. In its simplest definition, ovarian cancer that recurs within 6 months after responding to platinum-based chemotherapy is called platinum-resistant. Standard treatment options are limited, response rates are low, and survival is generally short. A new treatment demonstrating a genuine survival benefit is therefore considered a striking development for this population.

Presented at ESMO 2025 as abstract LBA3, ENGOT-ov65 / KEYNOTE-B96 was a phase 3 trial showing, for the first time in this setting, that an immune checkpoint inhibitor (pembrolizumab, Keytruda) produced a significant overall survival (OS) improvement . The trial involved 643 platinum-resistant patients, with weekly paclitaxel ± bevacizumab included in treatment.

Study Design and Patient Population

In this phase 3, randomized, double-blind study of 643 patients, 86% had high-grade serous histology and 7.8% had clear-cell histology. Approximately 73.3% had also received bevacizumab before enrollment.

Patients were randomized to two arms:

• Experimental arm: Pembrolizumab + weekly paclitaxel ± bevacizumab
• Control arm: Placebo + weekly paclitaxel ± bevacizumab

The two main endpoints were progression-free survival (PFS) and overall survival (OS) .

📊 Findings: What Do the Numbers Tell Us?

• At the first interim analysis (15.6 months of follow-up): PFS in the overall population was 8.3 months vs 6.4 months . This means a 30% reduction in disease progression risk (HR 0.70, p<0.0001) .
• In PD-L1-positive (CPS ≥1) patients: PFS was 8.3 months versus 7.2 months (HR 0.72, p=0.0014).
• At the second interim analysis (26.6 months of follow-up): OS was significantly prolonged in the PD-L1-positive group: 18.2 months vs 14.0 months (HR 0.76, p=0.0053).

PD-L1 and Bevacizumab Subgroups

The difference did not change according to bevacizumab use:

• With bevacizumab: HR 0.75 (95% CI: 0.58–0.97)
• Without bevacizumab: HR 0.75 (95% CI: 0.51–1.11)

Pembrolizumab's survival advantage therefore appears preserved regardless of bevacizumab use .

⚠️ Safety and Tolerability

Treatment-related grade ≥3 adverse events were reported in 67.5%of the experimental arm versus 55.3% of controls. This difference was considered clinically manageable.

The most common adverse effects were neutropenia, fatigue, neuropathy, and hypothyroidism. The study team nevertheless described the overall safety profile as "manageable".

DROZDOGAN Academy Commentary

• The first overall survival (OS) signal: The first significant OS benefit from immunotherapy in ovarian cancer suggests the immune system could again become a central player in this tumor type. This finding challenges the paradigm, particularly in a setting where immunotherapy has long failed.
• The biological meaning of the numerical difference: PFS of 8.3 versus 6.4 months and OS of 18.2 versus 14 months may initially seem modest, but in a platinum-resistant population they mean a 25% reduction in death risk . A difference of this magnitude is a clinically meaningful advance for these patients.
• The tumor microenvironment message: Weak responses in PD-L1-negative patients highlight the dominant role of immune evasion. This suggests a need to develop combinations that reprogram the microenvironment , for example with anti-VEGF agents, DNA damage response inhibitors, or ADCs.
• Implications for clinical practice: Pembrolizumab + paclitaxel ± bevacizumab emerges as a feasible option, particularly for more heavily treated, PD-L1-positive patients. However, patient selection is critical because of high-grade toxicity rates.
• Looking ahead: These results suggest that the paradigm of chemotherapy as the only option in platinum-resistant disease may gradually be broken. The integration of immunotherapy, ADCs, and targeted agents based on biological rationale will be a key area of future research.

🔗 Further Reading: Other Advances in Platinum-Resistant Ovarian Cancer

Alongside immunotherapy's survival signal, agents targeting other biological pathways are also attracting attention. For example, the phase 3 ROSELLA studyshowed that combining the glucocorticoid receptor blocker relacorilant with nab-paclitaxel significantly extended progression-free and overall survival in the same population. One approach strengthens the immune system while the other suppresses the stress response to overcome tumor resistance. Together, these could open the way to combination strategies focused on the "stress–immune axis" .

Conclusion: A Small Step With Major Meaning

KEYNOTE-B96 marks a milestone in platinum-resistant ovarian cancer. Although its OS improvement was not revolutionary, it brought immunotherapy in ovarian cancer back into focus .

The central question is now: how should combinations that amplify this signal—for example, ADC + IO + anti-VEGF triplets—be designed? ESMO 2025 provided a promising starting point for answering it.