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.

Early clinical trial data suggests that topoisomerase-1 payload ADCs retain efficacy in patients previously treated with mirvetuximab. Because mirvetuximab has a different cytotoxic payload, this indicates that targeting the same receptor (FR-alpha) with a different type of toxin is a viable sequencing strategy.

A "tsunami" of antibody-drug conjugates (ADCs) are in development for ovarian cancer, but many share the same TOP1 inhibitor payload. This creates a significant future clinical challenge: after a patient progresses on one such ADC, it is unknown if another with the same payload will be effective, creating an urgent need for sequencing data.

When sequencing antibody-drug conjugates, clinical experience suggests that resistance to the chemotherapy payload is a primary driver of failure. Therefore, oncologists tend to avoid using another ADC with the same payload consecutively, preferring to switch both target and payload if possible.

Experts question the efficacy of sequencing ADCs like EV (Nectin-4 target) and DV (HER2 target) because they share the same MMAE chemo payload. Since resistance is often tied to the payload, not the target antibody, switching targets may not overcome resistance, though anecdotal responses have been observed.

When planning treatment for patients who will receive multiple antibody-drug conjugates (ADCs), the prevailing clinical strategy is to focus on alternating the drug's payload (e.g., a tubulin inhibitor vs. a topoisomerase I inhibitor). This approach is believed to be more effective at overcoming resistance than alternating the cell-surface target.

Rather than moving through distinct lines of therapy, a future strategy could involve an "ADC switch." When a patient progresses on an ADC-IO combination, the IO backbone would remain while the ADC is swapped for one with a different, non-cross-resistant mechanism, adapting the treatment in real-time.

Emerging data shows that a second ADC, particularly one with the same payload, often has limited efficacy. This suggests clinicians must be highly strategic in selecting the first ADC, as it may be their most impactful opportunity for this class of drugs.

As multiple effective Antibody-Drug Conjugates (ADCs) become available, the primary clinical challenge is no longer *if* they work, but *how* to use them best. Key unanswered questions involve optimal sequencing, dosing for treatment versus maintenance, and overall length of therapy, mirroring issues already seen in breast cancer.