Academic Article, April 2026

Strategic Directions in Overcoming Platinum-Resistant Ovarian Cancer: A Paradigm Shift

Asst.Prof. Yuthasak Suphasynth
Department of Obstetrics and Gynaecology,Faculty of Medicine, Prince of Songkla University

          For decades, the management of Platinum-Resistant Ovarian Cancer (PROC) has been constrained by a therapeutic plateau, where sequential non-platinum chemotherapy (weekly paclitaxel, PLD, gemcitabine, or topotecan) with or without bevacizumab yields modest ORR of 10%–15%. With a median PFS of only 3–4 months and survival stagnated at 12 months [1], there is a critical imperative to transition toward biomarker-driven interventions

          The first major milestone in this strategic evolution was the landmark AURELIA trial [2], which established the combination of bevacizumab with non-platinum chemotherapy as a standard of care. By administering bevacizumab at 10 mg/kg every two weeks (or 15 mg/kg every three weeks) alongside agents like weekly paclitaxel, pegylated liposomal doxorubicin, or topotecan, researchers achieved a doubling of the median PFS to 6.7 months compared to 3.4 months with chemotherapy alone (HR = 0.48; 95% CI, 0.38–0.60; p < 0.001) and significantly improved the ORR from 11.8% to 27.3% (p < 0.001). Although the median OS of 16.6 months did not reach statistical significance over the control arm (p = 0.174), the regimen’s impact on disease control remains foundational. Practitioners using this strategy must remain vigilant regarding vascular side effects such as hypertension, proteinuria, and the rare but serious risk of gastrointestinal perforation.

          Following the success of anti-angiogenesis, the focus shifted toward the DNA damage response (DDR) pathway through PARP inhibitors. Trials like Study 42 explored their utility in patients who had failed multiple prior lines of therapy. In this study, olaparib (400 mg BID) demonstrated an ORR of 30% and a median DoR of 8.0 months specifically within the platinum-resistant population [3]. While these agents provided a targeted alternative, current guidelines generally do not recommend PARP inhibitor monotherapy for recurrent disease outside of specific molecular contexts. This was further evidenced by the NRG-GY005 trial, where the combination of olaparib and cediranib failed to show statistical superiority over standard chemotherapy in final survival analyses [4].

          The modern gold standard in PROC management is the rise of Antibody-Drug Conjugates (ADCs), led by mirvetuximab soravtansine (MIRV). Strategic development began with the Phase II SORAYA trial, where MIRV (6 mg/kg adjusted ideal body weight) elicited substantial activity in FRα-high patients, yielding an ORR of 32.4% and a median DoR of 6.9 months [5]. This was confirmed by the Phase III MIRASOL trial, where MIRV significantly outperformed conventional chemotherapy. Updated analysis at a 30.5-month follow-up showed a median OS of 16.85 months versus 13.34 months (HR = 0.68) and a median PFS of 5.62 months Notably, MIRV nearly tripled the ORR to 42.3% compared to 15.9% with conventional agents [6,7].  Simultaneously, the DESTINY-PanTumor02 trial established trastuzumab deruxtecan (T-DXd) (5.4 mg/kg every 3 weeks) as a potent option for HER2-expressing tumors. In the ovarian cancer cohort, T-DXd achieved an ORR of 45%, which increased to 63.6% in IHC 3+ patients, with a median OS of 20.0 months (95% CI 3.8–NR) [8]. These successes require a multidisciplinary approach to manage unique toxicities, such as MIRV-associated keratopathy and T-DXd-related interstitial lung disease.

          The year 2025 marked the successful entry of immunotherapy into the PROC arena through the KEYNOTE-B96 (ENGOT-ov65) trial [9]. This Phase III study revolutionized the field by combining pembrolizumab (400 mg IV every six weeks for up to 18 cycles) with weekly paclitaxel (80 mg/m² on days 1, 8, and 15 of each 21-day cycle), with or without bevacizumab. In the PD-L1 positive population (CPS ≥1), the triplet regimen demonstrated a median PFS of 8.3 months compared to 7.2 months in the placebo arm (HR = 0.75; 95% CI, 0.61–0.91). Furthermore, it achieved a significant overall survival advantage with a median OS of 18.2 months compared to 14.0 months in the chemotherapy-only group (HR = 0.76; 95% CI, 0.61–0.94; p = 0.0053). Building on these results, the FDA granted approval on February 10, 2026, for pembrolizumab with paclitaxel with or without bevacizumab for CPS ≥1 patients, alongside the 22C3 pharmDx companion diagnostic [10]. This milestone confirms the synergy of checkpoint inhibitors and taxanes in inducing immunogenic cell death. However, practitioners must remain vigilant for immune-mediated toxicities, such as hypothyroidism, hyperthyroidism, colitis, pneumonitis, and hepatitis, which require prompt management alongside the known safety profile of weekly paclitaxel.

          In conclusion, the management of PROC has moved away from a “one-size-fits-all” approach toward a highly curated, biomarker-first strategy. The timeline of progress moving from the anti-angiogenic foundations of AURELIA to the genomic precision of PARP inhibitors, the targeted potency of the MIRASOL and DESTINY-PanTumor02 ADCs, and the immunological breakthroughs of KEYNOTE-B96 represents a new era of optimism.

References

1. Pujade-Lauraine E, Banerjee S, Pignata S. Management of platinum-resistant, relapsed epithelial ovarian cancer and new drug perspectives. J Clin Oncol 2019;37:2437-2448.

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3. Domchek SM, Aghajanian C, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M,et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol Oncol. 2016;140(2):199-203.

4. Lee JM, Brady MF, Miller A, Moore RG, MacKay H, McNally L, et al. Cediranib and Olaparib Combination Compared With Cediranib or Olaparib Alone, or Chemotherapy in Platinum-Resistant or Primary Platinum- Refractory Ovarian Cancer: NRG-GY005. J Clin Oncol. 2024 Dec 20;42(36):4305-16.

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7. Van Gorp T, Angelergues A, Konecny G, et al. Final overall survival analysis among patients with FRα-positive, platinum-resistant ovarian cancer treated with mirvetuximab soravtansine vs investigator’s choice chemotherapy in the phase 3 MIRASOL (GOG 3045/ENGOT-ov55) study. Presented at: Society of Gynecologic Oncology (SGO) 2025 Annual Meeting on Women’s Cancer; March 14-17, 2025; Seattle, WA. Abstract 939696

8. Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee S, González-Martin A, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol 2023;41(suppl 17):abstr LBA3000.

9. Colombo N, Zsiros E, Sebastianelli A, Bidzinski M, Gallardo Araneda CE, Matanes E, et al. Pembrolizumab plus weekly paclitaxel with or without bevacizumab significantly improves progression-free and overall survival in platinum-resistant ovarian cancer: results from the randomized, double-blind phase III ENGOT-ov65/KEYNOTE-B96 trial. Ann Oncol 2025;36(suppl 5):abstr LBA3.

10. U.S. Food and Drug Administration. FDA approves pembrolizumab with chemotherapy for platinum-resistant ovarian cancer [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2026 Feb 10 [cited 2026 Feb 11]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-paclitaxel-platinum-resistant-epithelial-ovarian-fallopian-tube-or