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New analyses of the PICCOLO trial provided evidence of the efficacy of mirvetuximab soravtansine-gynx (MIRV) in patients with platinum-sensitive ovarian cancer, but also that ocular toxicity is a treatment-emergent adverse event.

Investigators presented the results of three analyses at the European Society for Medical Oncology (ESMO) Gynaecological Cancers Congress 2025 in June. These analyses demonstrated different aspects of MIRV’s clinical profile: a final efficacy analysis showed improved overall survival outcomes, a genomic subgroup analysis demonstrated sustained efficacy across homologous recombination deficiency (HRD) status subgroups, and a separate safety analysis revealed potential ocular toxicity, including an increased risk for cataract surgery.

Addressing an Unmet Clinical Need

Angeles Alvarez Secord, MD, of Duke Cancer Institute, Durham, North Carolina, noted in her presentation that patients with platinum-sensitive ovarian cancer who have received multiple prior therapies, particularly those who have progressed on PARP inhibitors, face a challenging clinical landscape.

Secord explained that MIRV, a first-in-class antibody-drug conjugate targeting folate receptor alpha (FRα), has already demonstrated efficacy in platinum-resistant ovarian cancer. The PICCOLO trial (NCT05041257) was specifically designed to evaluate its potential in the platinum-sensitive setting, where patients typically have better prognosis but still face diminishing returns with successive lines of therapy.

Relationship Between HRD Status and Treatment Response

Ane Oaknin, MD, of Vall d’Hebron University Hospital, Barcelona, Spain, who was the lead author of the genomic subgroup analysis examining the relationship between HRD status and response to MIRV, said her research addressed a critical question in ovarian cancer treatment, as HRD status has become an increasingly important biomarker for guiding therapeutic decisions.

Jean-Emmanuel Kurtz, MD, of ICANS - Institut de Cancérologie Strasbourg Europe, Strasbourg, France, who served as the discussant for this presentation, emphasized the complexity of ovarian cancer biology, drawing parallels between ovarian cancer and “a jigsaw puzzle with different shapes.” He explained that some tumors are wild-type BRCA, some are HRD, some have genomic and somatic alterations in BRCA, and some fall into a gray zone.

Among the 302 patients assessed for eligibility in PICCOLO, 152 had evaluable HRD test results using the FoundationOne CDx assay. The findings revealed that 70 patients (46%) were HRD-positive, while 64 (42%) were FRα-positive. Only 27 patients (18%) were positive for both markers, and no correlation was observed between HRD status and FRα expression.

“FRα expression was consistent across the HRD subgroups, with 40% of HRD-positive and 45% of HRD-negative tumors being FRα positive,” Oaknin explained during her presentation.

Of the 38 patients with known HRD status who were enrolled in the study, 19 (50%) were HRD-positive. Despite similar exposure to PARP inhibitors (84% vs 79%) and bevacizumab (68% vs 63%) between HRD-positive and HRD-negative groups, patients with HRD-positive tumors demonstrated a numerically higher objective response rate (58% vs 42%). They also experienced a shorter median duration of response (5.80 vs 8.31 months) and similar median progression-free survival (6.18 vs 6.90 months).

Final Analysis Shows Improved Long-term Outcomes

The final analysis of the PICCOLO trial, presented by Secord, who served as the lead author, provided mature overall survival data with a median follow-up of 26.6 months. In her presentation, Secord highlighted that the patients included in the final analysis were heavily pretreated, with 81% having received prior PARP inhibitor therapy and 75% having progressed on PARP inhibitors. The trial enrolled 79 patients with FRα-positive (≥ 75% of cells with ≥ 2+ membrane staining) platinum-sensitive ovarian cancer who had received at least two prior lines of platinum-based therapy.

The primary endpoint of investigator-assessed objective response rate was met at 51.9% (95% CI, 40.4-63.3), with a median time to response of 1.6 months. The median duration of response was 8.3 months (95% CI, 5.6-10.8), and the median progression-free survival was 6.9 months (95% CI, 5.9-9.6).

The median overall survival reached 27.2 months (95% CI, 23.8-NA), with an estimated 24-month survival probability of 60%. The overall survival benefit was consistent across all subgroups, including those with PARP inhibitor-resistant disease, who achieved a response rate of 45.8%. The overall survival among patients who had progressed on prior PARP inhibitor therapy was 27.04 months.

Manageable Adverse Events, but Possible Ocular Toxicity

Both analyses of data from the PICCOLO trial confirmed the manageable safety profile of MIRV. In the final analysis, the most common treatment-emergent adverse events included resolvable ocular events such as blurred vision (63%) and dry eye (37%), low-grade gastrointestinal effects (nausea, 37%; diarrhea, 30%), and peripheral neuropathy (29%). Only one additional grade 4 treatment-emergent adverse event was reported in the final analysis, a grade 4 cataract that was deemed not related to study treatment in a patient with preexisting cataracts.

In contrast to the adverse events seen in those two analyses, the separate retrospective safety analysis revealed that cataract surgery may be more common than previously recognized in patients receiving MIRV. Jordyn Silverstein, MD, of the University of California Los Angeles (UCLA), presented this and other findings of this analysis for which she was the lead author.

Silverstein and colleagues conducted this analysis independently at UCLA using their institutional data from 2021-2023 to specifically investigate cataract surgery incidence, which had not been systematically reported in the major clinical trials.

In this retrospective cohort study of 49 MIRV-treated patients matched with 49 control individuals, the incidence of cataract surgery following ovarian cancer diagnosis was significantly higher in the MIRV-exposed group (40.8% vs 8.1%; P = .001). When specifically examining cataracts that developed after starting MIRV treatment, 38% of MIRV-exposed patients developed cataracts, with a median time to cataract surgery of 17.5 months after initiation of MIRV treatment.

“After controlling for age, hypertension, diabetes, and smoking history, MIRV exposure was associated with 12 times the odds of cataract surgery,” Silverstein noted in her presentation.

The median time to cataract surgery after MIRV exposure was 1.5 years, with 60% of patients exposed to MIRV for more than 6 months requiring cataract surgery.

In addition, the study demonstrated that cataract surgery could be safely performed during MIRV treatment, with 40% of patients experiencing no treatment delays and an average delay of only 1 week when delays occurred.

Silverstein noted that the etiology of the association between MIRV exposure and the odds of cataract surgery is likely multifactorial, potentially involving MIRV itself, increased ophthalmologic monitoring, and the prophylactic ocular steroid drops required with each treatment cycle.

Understanding MIRV-Associated Ocular Toxicity

Silverstein explained that the ocular effects associated with MIRV appear to be payload-mediated rather than target-related as folate receptor alpha expression is not found in normal ocular tissues. Other antibody-drug conjugates with DM4 payloads have historically shown similar ocular toxicities, including cataracts, she noted.

Ignacio Romero, MD, of Instituto Valenciano de Oncologia, Valencia, Spain, who served as discussant for the cataract surgery presentation, emphasized the importance of distinguishing between ocular symptoms and their underlying causes. He explained that blurred vision is a symptom commonly caused by corneal keratopathy (corneal microcysts), while cataracts specifically affect the lens.

Romero highlighted that cataracts represent a significant global health burden, affecting 94 million people worldwide and serving as the leading cause of blindness. In cancer patients specifically, the mean age for cataract surgery is typically 71 years, with an average duration of 4.3 years from cancer diagnosis to surgery. The MIRV-associated cataract surgery data showed a notably shorter timeframe.

“This is the first study to underline the importance of cataract surgery in ovarian cancer patients and the potential relation of antibody-drug conjugate ocular toxicity to surgical implications,” Romero noted.

He emphasized that the study appropriately accounted for established cataract risk factors, including diabetes, hypertension, and obesity, but highlighted that the retrospective design is a key limitation of the study.

Current FDA recommendations require patients receiving MIRV to use prophylactic corticosteroid eye drops with each treatment cycle, one drop six times daily from the day before infusion through day 4, then four times daily through day 8.

Silverstein emphasized that although these steroids help manage acute ocular effects like keratopathy, they may contribute to long-term cataract development, as corticosteroids are a known risk factor for cataract formation.

Romero acknowledged several limitations in understanding MIRV-associated cataracts, including potential overtreatment due to increased ophthalmologic surveillance and unknown mechanisms underlying the relationship between corneal effects and lens damage. Despite these uncertainties, he emphasized the clinical benefits of cataract surgery, which is cost-effective and associated with a 30% reduced risk of developing dementia, potential positive effects on depression, and improved sleep regulation.

“More research is needed to understand the necessity of steroid eye drops for primary prophylaxis,” Silverstein noted.

Clinical Implications and Future Directions

The PICCOLO trial results provide evidence of MIRV efficacy in patients with platinum-sensitive ovarian cancer, regardless of HRD status, and particularly in those who have exhausted standard treatment options. Kurtz said. At the same time, he cautioned that confirmation of this in larger trials is needed.

Oaknin concluded that the PICCOLO trial demonstrates that targeted approaches such as MIRV can achieve meaningful outcomes regardless of underlying genomic characteristics, adding that “FRα and HRD are both clinically actionable biomarkers that should be evaluated further to inform treatment plans for appropriate patients with ovarian cancer.”

Oaknin reported financial relationships with Roche, AstraZeneca, PharmaMar, Agenus, Clovis Oncology, Corcept Therapeutics, Deciphera Pharmaceuticals, Daiichi Sankyo, Debiopharm, Eisai Europe, Exelixis, F. Hoffmann-La Roche, Genmab A/S, GSK, ImmunoGen, iTeos Therapeutics, Merck Sharp & Dohme, Mersana Therapeutics, Myriad Genetics, Novocure GmbH, OncXerna Therapeutics, PharmaMar, Regeneron Pharmaceuticals, Shattuck Labs, Seagen Inc/Pfizer, Sutro Biopharma, and Zentalis Pharmaceuticals.

Secord reported financial relationships with AbbVie, Aravive, AstraZeneca, Clovis Oncology, Eisai, Ellipses Pharma, Roche/Genentech, Genmab, GSK, ImmunoGen, Karyopharm Therapeutics, Merck, Mersana Therapeutics, Myriad, OncoQuest Pharmaceuticals/Canariabio, Seagen, TORL Biotherapeutics, VBL Therapeutics, Zentalis Pharmaceuticals, The GOG Foundation, Amgen, Johnson & Johnson, Up ToDate, Research to Practice, Clinical Care Options, Curio, HMP Global, and Imedex.

Kurtz reported financial relationships with AstraZeneca, Eisai, GSK, Chugai Pharma, PharmaMar, and MSD.

Silverstein reported no financial relationships.

Romer reported financial relationships with Roche, PharmaMar, Clovis, GSK, AstraZeneca, Regeneron, and PharmaMar.

Christos Evangelou, PhD, is a freelance medical writer and science communications consultant.