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Summary
Ovarian cancer is diagnosed in approximately 20,000 women annually in the US and remains the most lethal gynecologic malignancy — largely because most cases present at advanced stage. PARP inhibitor maintenance has substantially extended progression-free survival in BRCA-mutated and HRD-positive tumors, and the antibody-drug conjugate mirvetuximab soravtansine has become the first new drug in years to show a survival benefit in platinum-resistant disease. In 2026, trials are addressing PARP resistance, expanding ADC targets, and probing the limited but potentially growing role of immunotherapy in ovarian cancer.
PARP Inhibitor Maintenance: Established and Expanding
PARP inhibitors (PARPi) exploit homologous recombination deficiency (HRD) — the inability of tumor cells with BRCA1/2 mutations or other HRD to repair DNA double-strand breaks via homologous recombination, making them exquisitely sensitive to PARP inhibition through synthetic lethality.
Three PARPi are FDA-approved for ovarian cancer: olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca, withdrawn). Olaparib + bevacizumab maintenance (PAOLA-1 trial) and niraparib maintenance (PRIMA trial) have both demonstrated significant PFS benefits in HRD-positive tumors after first-line platinum-based chemotherapy. BRCA1/2-mutated patients derive the greatest benefit, but HRD-positive/BRCA-wild-type tumors also show meaningful benefit.
In 2026, critical questions being addressed in trials include: How to manage and overcome acquired PARPi resistance (BRCA reversion mutations, restored HRD, drug efflux pumps); whether combining PARPi with ATR inhibitors (ceralasertib, berzosertib) can overcome resistance; and whether second-line PARPi rechallenge is effective after a treatment break.
Mirvetuximab Soravtansine: ADC for FRα-High Disease
Mirvetuximab soravtansine (Elahere, ImmunoGen) is an antibody-drug conjugate targeting folate receptor alpha (FRα), which is overexpressed in ~35% of high-grade serous ovarian cancers. The antibody delivers a potent maytansinoid cytotoxin (DM4) directly to FRα-expressing tumor cells, minimizing systemic toxicity.
The MIRASOL Phase 3 trial compared mirvetuximab soravtansine to investigator's choice chemotherapy in platinum-resistant ovarian cancer with high FRα expression. Mirvetuximab showed a 35% reduction in the risk of death (OS HR 0.67) and a 35% improvement in PFS — representing the first survival benefit seen in a Phase 3 platinum-resistant ovarian cancer trial in over a decade. FDA granted full approval in March 2024. Current trials (GLORIOSA, PICCOLO) are evaluating mirvetuximab in platinum-sensitive disease as maintenance and in combination with bevacizumab and carboplatin.
Emerging ADC Targets and Combinations
The success of mirvetuximab has accelerated ADC development across multiple targets in ovarian cancer:
Upifitamab rilsodotin (UpRi): Targets NaPi2b (sodium-dependent phosphate transporter), expressed in ~80% of ovarian cancers — a broader population than FRα. Phase 1/2 UPLIFT trial data showed a 35% overall response rate in heavily pre-treated patients. Phase 3 is now enrolling.
Trastuzumab deruxtecan (T-DXd) for HER2-positive ovarian cancer: ~30% of ovarian cancers express HER2. The DESTINY-PanTumor02 basket trial included ovarian cancer patients with HER2 positivity, showing a 45% ORR. Phase 2/3 trials specific to ovarian cancer are planned.
RINA-TOPO1 inhibitor ADCs: A new generation of ADCs using topoisomerase I inhibitor payloads (like deruxtecan) with various antibody targets are entering Phase 1/2 for ovarian cancer, based on the bystander killing effect — the payloads can diffuse to kill adjacent tumor cells even if they don't express the target antigen.
Immunotherapy in Ovarian Cancer
High-grade serous ovarian cancer has historically been considered "immunologically cold" — low tumor mutational burden, few tumor-infiltrating lymphocytes, and multiple immunosuppressive mechanisms including TGF-beta, IDO, and regulatory T cells in the tumor microenvironment. Single-agent checkpoint inhibitors showed only 8–15% response rates in unselected populations.
However, subsets of ovarian cancer patients do respond durably. Trials are now focused on combination strategies to "warm up" cold tumors: PARP inhibitor + PD-1/PD-L1 inhibitor combinations (based on evidence that PARPi increases mutational burden and PD-L1 expression); anti-VEGF (bevacizumab) + checkpoint inhibitor (targeting immunosuppressive tumor vasculature); and neoantigen vaccine approaches targeting patient-specific tumor mutations. The DUO-O trial (olaparib + durvalumab + bevacizumab) is reporting results in 2025–2026.
Key Takeaways
- PARPi maintenance extends PFS substantially in BRCA-mutated and HRD-positive ovarian cancer; trials are addressing acquired resistance mechanisms.
- Mirvetuximab soravtansine is the first drug in years to show a survival benefit in platinum-resistant ovarian cancer (FRα-high patients).
- New ADCs targeting NaPi2b and HER2 are in Phase 2/3 trials, potentially extending the ADC benefit to broader ovarian cancer populations.
- Immunotherapy alone has limited activity in ovarian cancer, but combinations with PARPi, bevacizumab, and neoantigen vaccines are in late-stage testing.
- HRD biomarker testing and FRα expression testing are now essential to guide treatment selection in advanced ovarian cancer.