Topoisomerase I payloads in ADCs carry a high risk of neutropenia, a toxicity that has caused previous trials to fail. Future Phase 3 studies, particularly in prostate cancer, must incorporate proactive management strategies like prophylactic GCSF to mitigate this risk, which is considered a critical success factor.
Initial ADCs targeting PSMA in prostate cancer were hampered by the neurotoxicity of MMAE payloads and inefficient linker technology. This limited deliverable dosage, causing trials to fail for technical reasons rather than a flawed biological target, paving the way for newer, better-designed ADCs.
The novel ADC ABBV-969 targets both PSMA and STEEP-1. This approach addresses tumor heterogeneity, as a combined 36% of patients express only one of these targets. By providing two ways for the drug to enter cancer cells, this strategy may significantly broaden its efficacy across the patient population.
Counterintuitively, data suggests that prostate cancer patients who progressed on PSMA-targeted radioligand therapy can still achieve deep responses to a PSMA-targeting ADC. This may be because resistant tumors become more proliferative, increasing their sensitivity to the ADC's cytotoxic topoisomerase payload, which has a different mechanism of action.
As potent ADCs prove effective, the current paradigm of treating until disease progression is unsustainable due to cumulative toxicity. Experts urge trial designers to be "brave" and prospectively investigate optimal, fixed treatment durations sooner rather than later, shifting the goal from indefinite therapy to achieving a deep remission.
Instead of replicating the ADC and checkpoint inhibitor combination successful in other cancers, experts suggest a more "sophisticated" approach for prostate cancer. The next step should be combining ADCs with T-cell engagers, which have shown greater single-agent efficacy in this specific disease, potentially leapfrogging a less effective strategy.