While traditional markers are limited by their elevated levels in non-cancerous conditions, mucins offer a new possibility for targeted treatment in ovarian cancer. This review comprehensively described the potential of mucins for the generation of ADC therapy, highlighting their importance in the quest to improve the outcome of ovarian cancer patients.

In OC, primary chemotherapy, paclitaxel carboplatin, bevacizumab, and PARP inhibitors have shown prolonged progression-free survival and a favorable overall response rate compared to conventional treatments...Recently, mirvetuximab soravtansine, an alpha-folate receptor (FRα)-targeted antibody-drug conjugate (ADC), was approved by the US Food and Drug Administration for patients with FRα-positive recurrent epithelial OC (EOC)...Ongoing clinical trials are evaluating ADCs targeting FRα and human epidermal growth factor receptor 2, trophoblast cell surface antigen-2, sodium-dependent phosphate transport protein 2B, and cadherin-6 in Phase II/III studies. In this review, we summarize the existing evidence supporting the use of ADCs in OC, discuss ongoing clinical trials and preclinical studies, and explore the potential of these innovative agents to address the challenges in OC treatment.

P1, N=62, Completed, Mersana Therapeutics

P1, N=142, Completed, Mersana Therapeutics

P1/2, N=252, Not yet recruiting, Jilin Cancer Hospital; Jilin Cancer Hospital

P1/2, N=252, Recruiting, MediLink Therapeutics (Suzhou) Co., Ltd. | Not yet recruiting --> Recruiting

P1/2, N=252, Not yet recruiting, MediLink Therapeutics (Suzhou) Co., Ltd.

P1/2, N=100, Recruiting, Tubulis GmbH | Not yet recruiting --> Recruiting

P1, N=31, Terminated, Mersana Therapeutics | Phase classification: P1b --> P1

P1/2, N=523, Active, not recruiting, Mersana Therapeutics | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2

P3, N=20, Terminated, Mersana Therapeutics | N=350 --> 20 | Trial completion date: Mar 2025 --> Sep 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Sep 2024 --> Sep 2023; Study Terminated by Sponsor

P1, N=31, Terminated, Mersana Therapeutics | N=48 --> 31 | Trial completion date: Mar 2025 --> Oct 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Nov 2024 --> Oct 2023; Study Terminated by Sponsor

P1b, N=31, Terminated, Mersana Therapeutics | N=120 --> 31 | Active, not recruiting --> Terminated; discontinued development program

Further validation is warranted in terms of protein expression. Our results underscore the potential value of gene expression profiling to identify new targets and improve patient selection in the context of NSCLC-BM ADC therapy.

P1, N=48, Active, not recruiting, Mersana Therapeutics | Recruiting --> Active, not recruiting

P3, N=350, Active, not recruiting, Mersana Therapeutics | Recruiting --> Active, not recruiting

In ovarian cancer, mirvetuximab soravtansine, an ADC targeting alpha-folate receptor (FRα), received US Food and Drug Administration (FDA) accelerated approval in November 2022 after data from the single-arm phase III SORAYA trial. A second ADC targeting FRα, STRO-002, received FDA fast track designation in August 2021. Multiple studies with upifitamab rilsodotin, an ADC comprising a NaPi2B-binding antibody, are underway. In cervical cancer, tisotumab vedotin, an ADC-targeting tissue factor, received FDA accelerated approval in September 2021 after the phase II innovaTV 204 trial...Trastuzumab-deruxtecan (T-DXd), an ADC targeting human epidermal growth factor receptor 2 (HER2), is currently approved for HER2-positive and HER2-low breast cancer and shows promise in endometrial cancer. Like all anticancer treatments, the decision for a patient to undergo therapy with an ADC is a personal choice that balances the potential benefits with the side effects and requires thorough and compassionate support of their physician and care team and shared decision making.

NCT04907968. Clinical trial information: NCT04907968.

Background: Biomarker driven therapies are increasingly being used for gynecologic cancers, with mirvetuximab soravtansine, a Folate Receptor alpha (FRa) targeting antibody drug conjugate (ADC) being a recent FDA approved agent for patients with FRa positive PROC... Based on this analysis of a limited sample size, there does not appear to be an association between FRa and NaPi2b expression, with the majority of NaPi2b positive samples not being FRa positive. Additionally, general NaPi2b prevalence and the correlation of expression between RNA and IHC suggest that NaPi2b may be a rational biomarker to integrate in RNA tumor panel testing. This research underscores the importance of early, comprehensive testing of all relevant biomarkers to guide therapy selection, and suggests that additional research is needed to evaluate the potential association between FRa and NaPi2b expression via IHC.

Patients who received bevacizumab in combination with their most recent platinum containing regimen are excluded...NCT05329545. Clinical trial information: NCT05329545.

P1b, N=120, Active, not recruiting, Mersana Therapeutics | Trial primary completion date: Dec 2022 --> Mar 2023

Current evidence strongly supports the use of ADCs and ongoing clinical trials will provide further information into the potential of making these drugs part of current standard practice allowing patients to be treated with a higher level of personalized cancer care.

Emerging data from phase 1 and 2 clinical trials in ovarian cancer have suggested that NaPi2b can be successfully detected in patient biopsy samples using immunohistochemistry, and the NaPi2b-targeting antibody-drug conjugate under evaluation appeared to elicit therapeutic responses. The aim of this review is to examine literature supporting NaPi2b as a novel biomarker for potential treatment and patient selection in ovarian cancer and to discuss the critical next steps and future analyses necessary to drive the study of this biomarker and therapeutic targeting forward.

P1, N=48, Recruiting, Mersana Therapeutics | Phase classification: P1/2 --> P1 | Trial completion date: Jul 2024 --> Mar 2025 | Trial primary completion date: Nov 2023 --> Nov 2024

P1b/2, N=444, Recruiting, Mersana Therapeutics | Trial completion date: Dec 2023 --> Dec 2024

Patients who received bevacizumab in combination with their last platinum containing regimen are excluded... N/A - trial in progress

UPGRADE-A is the first cohort evaluating UpRi in combination with carboplatin in patients with PSOC who have received 1-2 prior lines of therapy. trialinprogress

Patients who received bevacizumab in combination with their last platinum containing regimen are excluded. TrialinProgress

UpRi is being evaluated in clinical trials, requiring either fresh or archival tissue for NaPi2b expression assessment. The high expression concordance rate seen suggests that NaPi2b remains consistent throughout chemotherapy treatment, supporting use of archival tissue for analysis.

Antigen presentation genes showed decreased expression in fresh samples, suggesting tumors may evade immune surveillance during disease progression. Clinical trial information: NCT03319628.

P3, N=350, Recruiting, Mersana Therapeutics | Not yet recruiting --> Recruiting

P1b, N=120, Active, not recruiting, Mersana Therapeutics | Recruiting --> Active, not recruiting