Gynecologic cancers, including ovarian, endometrial, and cervical cancers, are significant causes of cancer-related deaths, often diagnosed late and characterized by high relapse rates and therapy resistance. In recent years, two drug classes have shown promise in specific patient groups: immune checkpoint inhibitors (targeting PD-1/PD-L1) and PARP inhibitors. However, the most significant benefits are seen in patients with specific biomarkers, such as dMMR/MSI-H for immunotherapy and BRCA/HRD for PARP inhibition.
The combination of these therapies is a fascinating prospect, as PARP inhibition can increase DNA damage, activate the innate immune response (via cGAS–STING), boost interferon signaling, and make tumors more immunogenic. This effect might be further enhanced by PD-1/PD-L1 blockade, potentially creating a powerful synergy.
This narrative review searched MEDLINE, Embase, and ClinicalTrials.gov (2015-2025) for trials combining PARP inhibitors with anti-PD-1/PD-L1 agents in ovarian, fallopian tube, primary peritoneal, endometrial, or cervical cancers. The review had specific eligibility criteria, including efficacy endpoints and safety assessments in gynecologic cancer patients.
The review revealed several key findings:
- Ovarian Cancer: The most promising results were seen in ovarian cancer, particularly in patients with BRCA/HRD biology. Niraparib + pembrolizumab and olaparib + durvalumab showed encouraging responses, especially in HRD-positive tumors and platinum-sensitive relapse, respectively. The addition of bevacizumab may extend these benefits to non-BRCA patients.
- Frontline Maintenance: In newly diagnosed ovarian cancer, PARP+IO combinations have not shown superiority. Rucaparib + nivolumab maintenance did not improve outcomes, emphasizing the challenge of translating early-phase success to phase III trials in unselected patients.
- Endometrial Cancer: Overall, limited activity was observed in endometrial cancer. Olaparib + durvalumab and talazoparib + avelumab demonstrated modest activity, primarily in biomarker-enriched subgroups. This aligns with the understanding that endometrial cancer responds best to immunotherapy in dMMR/MSI-H settings.
Toxicities were generally manageable, but combination therapies, especially triplets, can increase treatment complexity and monitoring needs. The review highlights the following insights:
- The synergy between PARP inhibition and immune checkpoint blockade is biologically plausible, but clinical benefits are context-specific.
- Ovarian cancer, especially BRCA/HRD and platinum-sensitive cases, shows the most promising efficacy signals, where PARP inhibitors are inherently active.
- Intensifying frontline maintenance with PARP+IO is not yet supported by randomized trials in unselected populations.
- In endometrial cancer, the combination therapy seems most effective in molecularly selected groups.
In summary, combining PD-1/PD-L1 blockade with PARP inhibition is a promising strategy in gynecologic oncology, particularly in ovarian cancer with BRCA/HRD biology and platinum sensitivity. However, its role in frontline maintenance is unclear, and endometrial cancer responses are limited outside specific molecular contexts. The future of this approach lies in biomarker-driven trials, optimized sequencing, and regimens that balance efficacy with tolerability.
