Unlike immunotherapy, where re-challenge after progression is dubious, there is an emerging clinical practice of re-challenging patients with the same antibody-drug conjugate (ADC), such as enfortumab vedotin (EV), after a treatment break forced by toxicity. Anecdotally, patients are showing great responses, highlighting a key area for prospective data generation.

Real-world data shows that in platinum-sensitive ovarian cancer patients who have progressed on PARP inhibitors, subsequent platinum-based chemotherapy has a surprisingly low response rate of only 20%. This quantifies a significant opportunity for highly active ADCs to potentially replace platinum in this growing patient population.

For antibody-drug conjugates (ADCs) to make a meaningful impact in prostate cancer, the clinical development bar is exceptionally high. Merely showing activity in late-line settings is insufficient; the true measure of success is demonstrating superiority over the established chemotherapy standard, docetaxel.

The development of PARP-1 selective inhibitors like seriparib signals a shift in drug innovation. Instead of only chasing higher efficacy, these new agents aim for a more favorable toxicity profile (less GI toxicity, fewer dose discontinuations) to improve patient quality of life and treatment adherence.

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.

The TRILINX trial revealed Xevinapant's toxicity was so high that it forced reductions in standard, effective treatments like cisplatin and radiation. This compromised the foundational therapy, leading to worse patient outcomes and demonstrating a key risk in adding novel agents to established regimens.

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.

The REJOICE trial for an ADC in ovarian cancer exemplifies a critical trend: embedding multi-arm dose optimization studies. This approach identified a dose that maintained high response rates (57%) while significantly lowering rates of serious adverse events like ILD (from 6% to 3%), prioritizing patient safety.

Clinicians should avoid directly comparing the toxicity profiles of new ADCs, as the data often comes from different trial stages. A drug in a Phase 1 expansion cohort may appear more toxic than one with mature Phase 2 randomized data, making definitive safety assessments premature.