Over the past two years, the treatment of ovarian cancer has undergone a phase of “rewriting” rather than revolution: the central role of platinum has not changed, but a more precise biology has consolidated around the surgery-chemotherapy combination (HRD, FRα expression, molecular subtypes), and targeted drugs have entered the scene—especially antibody-drug conjugates (ADCs) and, in a niche, dual-target inhibitors of the MAPK/FAK pathway, which are redefining the options when chemotherapy alone is not enough. The most tangible example is mirvetuximab soravtansine (MIRV), an anti-folate receptor α ADC: after accelerated approval, confirmatory data from the MIRASOL trial showed significant benefits versus chemotherapy in platinum-resistant (FRα-positive) tumors, with an overall survival advantage (median ~16.5 vs ~12.8 months),
This consolidates MIRV as the new standard in that setting and also driving its adoption in combination with bevacizumab in selected settings. In FORWARD II and subsequent studies, the combination of MIRV and bevacizumab produced interesting response rates and durations, and even carboplatin triplets are exploring whether they can “restore” sensitivity in recurrent disease with high FRα expression; US guidelines have progressively incorporated this evidence. The ADC pipeline does not stop at FRα. Claudin-6 (CLDN6), an oncofetal antigen expressed in significant proportions of high-grade serous ovarian tumors, has generated a new generation of ADCs (e.g., TORL-1-23; other exatecan-based ones) with signs of activity in Phase I trials in previously treated patients, including platinum-resistant forms.
These preliminary but consistent data across multiple groups suggest that in the near future we may be able to segment the use of ADCs by target, as has already been done in other solid tumors. On the “chemotherapy + target” front, the most concrete advance concerns the low-grade subtype (LGSOC), biologically dependent on MAPK: in 2025, the FDA granted accelerated approval to the combination of trovatometinib (RAF/MEK) + defactinib (FAK) for KRAS-mutated LGSOC after systemic therapy, the first specific approval for this population—traditionally poor responders to chemotherapy. The clinical message is twofold: 1) it is always necessary to type the tumor (KRAS/NRAS/BRAF), 2) where chemotherapy had limited margins, a targeted doublet can change the therapeutic trajectory.
PARP1 inhibitors remain the cornerstone of post-platinum maintenance therapy in BRCA-mutated and/or HRD-positive patients, but the landscape has become more selective: recent regulatory history (withdrawals of indications in pretreated advanced settings) and long-term analyses have led to more targeted use, with attention to HRD definitions and cutoffs and resistance management (reversion mutations, fork stabilization). At the same time, interest in rational combinations (PARP+ATR, PARP+WEE1 or immunotherapy) is growing, but many of these strategies are still in the proof-of-concept stage, and daily clinical practice today favors careful biological selection rather than indiscriminate intensification. And what about immunotherapy?
Alone, it has yielded less than hoped for in high-grade epithelial cancer, partly due to the heterogeneity of the peritoneal immune microenvironment and mechanisms of “immune coldness.” TIME spatial studies show very diverse phenotypes, and functional research is beginning to map resistance drivers (e.g., tumor-derived IL-4 signaling) that could become new targets or biomarkers for recruitment. Meanwhile, some subtypes, such as clear cell carcinoma (OCCC), with genomic and immunological peculiarities, remain candidates for immune-centric strategies and dedicated trials. Finally, not all promises materialize: the anti-NaPi2b ADC upifitamab rilsodotin was discontinued after failing to meet the response endpoint, a reminder that the biology of ovarian cancer, especially platinum-resistant ovarian cancer, is as crucial as the drug load.
In short, “chemotherapeutic innovations” in the strict sense are less and more incremental (optimization of weekly taxanes, PLD, combinations with bevacizumab); the real practical innovation is the introduction of ADCs and, in a niche setting, doublets targeted to well-defined biology (high FRα; KRAS-mutated in LGSOC), while PARP inhibitors are being used more maturely and selectively. The direction of research is clear: better typing (high-quality HRD, FRα, CLDN6, histological subtype), using the “right” drugs at the right time, and abandoning empirical combinations not supported by rationale or biomarkers.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Rausch M et al. Signal Transduct Target Ther 2025; 10(17).
Silverstein J et al. Ther Adv Med Oncol 2025; 21(17):2143.
Kong B, Zheng B. J Hematol Oncol. 2025 Mar 18; 18:33.
McNulty M. Ovarian Cancer Guideline Updates 2024; 30(2):SP113
Emens LA, Romero P et al. J Immunother Cancer 2024; 12(6).
Mateiou C, Lokhande L et al. Fnpj Precis Oncol 2024; 8:148.
Tuninetti V et al. ESMO Open 2024; 9(11):103984.
