Beyond Tumor Accumulation in Oncology Peptide Drug Conjugates: A Critical Narrative Review of Release-Competent Exposure and a Stage-Gated Translational Roadmap

Peptide–drug conjugates (PDCs) combine peptide-mediated targeting or transport with a pharmacologically active payload. This critical narrative review organizes oncology PDC development around release-competent exposure (RCE): the connection between conjugate integrity, formation of an identified active compound, delivery to its tumor compartment, pharmacodynamic effect, and therapeutic margin. Tumor uptake or accumulation is distinguished from the concentration–time profile of an identified active species in its relevant compartment. PubMed, ClinicalTrials.gov, and regulatory sources informed the review through 15 September 2026; the recorded retrieval procedures were re-executed and archived on 24 October 2026. We distinguish payload-releasing PDCs from enzyme-potentiated prodrugs and non-cleaving modalities, assemble established, adapted, and conceptual exposure measures, and integrate analytical requirements into a stage-gated development framework. Clinical examples include zelenectide pevedotin, PEN-221, zoptarelin doxorubicin, ANG1005, and melflufen. Five preclinical illustrations and a separate calculation from published tissue AUCs show how different observations inform the framework. ADC-derived principles are qualified by PDC-specific disposition, while sparse tissue sampling, imaging, and modeling are evaluated as translational strategies. Use of these exposure measures within RCE remains hypothesis-generating and requires construct-specific validation; established PK quantities are not thereby validated clinical surrogate endpoints.