From histological and molecular pathology to the inclusion of antibody-drug conjugates in clinical practice against ovarian cancers: Mechanisms of action and pharmacological safety

Approximately 75% of the ovarian cancer (OC) patients are diagnosed in advanced stages and platinum-based chemotherapy presents severe side effects and high recurrence rates. This narrative review consolidates current knowledge and describes the pathophysiological characteristics of OC and how molecular aspects influence clinical outcomes of traditional and antibody-drug chemotherapies. Subsequently, a comprehensive picture regarding the current benefits identifies gaps and potential adverse risks of ADCs to treat OC. High-grade serous carcinomas, the most frequently diagnosed OCs, present TP53 and BRCA1/2 mutations, hypermethylation, and deregulation of retinoblastoma 1 and phosphatidylinositol 3-kinase (PI3K)/Akt/Ras pathways. After conventional treatment (surgery with or without systemic chemotherapy) and follow-up by CA125 levels, poly(ADP-ribose) polymerase inhibitors and hormone therapies were included. Unfortunately, approximately half of advanced patients who achieved a complete response following chemotherapy exhibit residual tumor(s). In this context, ADCs displayed marked cytotoxicity and incorporated a hypothesis-driven target identification strategy to recognize specific/tumor overexpressing-proteins. Independent clinical studies bibliographic searches in the PubMed database conducted between January 2020 and May 2025 revealed some ADCs have expanded progression-free survival and displayed partial/complete remission in OC patients at small doses if compared to traditional chemotherapies, suggesting acceptable safety profiles and potential synergism among cisplatin/carboplatin/paclitaxel/doxorubicin and ADC-based immunotherapies. A total of 18 clinical trials selected indicate (i) mild-to-moderate severity of side/adverse effects up to grade 2, (ii) low intervention or drug discontinuation, (iii) few drug-related deaths, and/or (iv) reversible toxicity. Thus, therapeutic performance of ADCs demonstrated that personalized treatment maximizes clinical benefits and improves efficacy for heterogeneous populations and polyclonal tumors.