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.

With multiple ADCs available, an emerging sequencing strategy is to alternate between different mechanisms of action, such as following a microtubule toxin-based ADC with a topoisomerase-1 inhibitor payload. This approach aims to avoid compounding specific toxicities, like neuropathy, and potentially circumvent resistance, though it is a strategy born from logic rather than clinical trial 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.

Patients whose ovarian cancer progresses on the folate-targeted ADC mirvetuximab may still respond to a subsequent folate-targeted ADC with a different cytotoxic payload. This suggests that the folate receptor alpha target remains viable and that resistance may be payload-specific, opening new sequencing strategies.

Retrospective data shows that using one Antibody-Drug Conjugate (ADC) after another, particularly those with the same class of payload like TOP1 inhibitors, results in a low response rate of 10-20%. This creates a significant unmet need and a major clinical challenge for patients who progress on a first-line ADC.

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.

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.

A promising future strategy for ovarian cancer involves combining two different ADCs. The key to this approach is selecting agents with distinct payloads (e.g., an anti-microtubulin and a TOPA-1 inhibitor) whose side effect profiles do not overlap. This could maximize anti-tumor efficacy while maintaining a manageable toxicity burden for patients, offering a novel combination paradigm.

Most new antibody-drug conjugates (ADCs) for ovarian cancer use the same topoisomerase-1 (Topo1) inhibitor payload. This similarity will likely prevent their sequential use due to cross-resistance, forcing clinicians into a "one-shot" scenario where they must choose the single best Topo1-based ADC upfront for a patient.