The introduction of ADCs into frontline ovarian cancer treatment creates a new challenge: conflicting biomarkers. A patient's tumor might be positive for both HER2 (an ADC target) and a BRCA mutation (a PARP inhibitor target), forcing clinicians to choose between two effective targeted therapies without clear guidance.

The treatment landscape for platinum-resistant ovarian cancer has rapidly evolved into a biomarker-driven paradigm. Clinicians must now test for and choose between therapies targeting distinct markers like folate receptor alpha (mirvetuximab), HER2 (T-DXd), and PD-L1 (pembrolizumab), requiring a sophisticated sequencing strategy.

Unlike in breast cancer, where HER2 IHC 2+ requires FISH confirmation, in gynecologic cancers an IHC 2+ result is often considered directly actionable for prescribing HER2-targeted ADCs like T-DXD. This reflects a different, less stringent clinical standard for biomarker-guided therapy in this setting.

Unlike early ADCs requiring high biomarker expression (e.g., mirvetuximab), next-generation agents show efficacy even in low-expressing tumors. This allows for broader, "all-comer" clinical trial inclusion criteria instead of biomarker-gated entry, potentially expanding patient access to these novel therapies.

A new wave of antibody-drug conjugates (ADCs) is transforming ovarian cancer treatment. These 'heat-seeking missiles' deliver potent chemotherapy payloads directly to tumor cells, achieving response rates from 23% to over 60% in biomarker-selected populations. This far surpasses the efficacy of conventional chemotherapy in resistant settings.

Despite concerns about cross-resistance from breast cancer data, experts would consider sequencing ADCs with the same payload (e.g., deruxtecan). The rationale is that even a diminished response rate (e.g., 30%) is still significantly better than the 15% seen with standard single-agent cytotoxics.

A surprising trend in ovarian cancer is the consistent efficacy of antibody-drug conjugates (ADCs) with a TOPA1 payload. Regardless of the specific cell surface target, these agents are achieving response rates around 50%, suggesting the payload's potency is the primary driver.

Although HER2 expression is rare in cervical cancer, it is a crucial biomarker to test for. In these uncommon cases, patients who have progressed on standard immunotherapy can achieve "wonderful responses" with trastuzumab deruxtecan (T-DXd), highlighting a powerful, targeted option for a population with high unmet need.

The standard HER2 tests were developed to identify HER2-positive tumors, not to precisely quantify low levels of expression. This creates a diagnostic challenge for identifying patients eligible for HER2-low targeted ADCs, requiring closer collaboration with pathology to interpret results that may be near the threshold, such as HER2-zero but with some minimal staining.