The PSMA paradox: How biology, androgen signaling, and therapy sequencing shape Lu-177 efficacy

Background Prostate-specific membrane antigen (PSMA)-directed radioligand therapy improves outcomes in advanced prostate cancer, yet appears less effective when moved earlier in the disease course. Objectives To explain the “PSMA paradox” by integrating clinical trial patterns with biologic and physical determinants of radioligand efficacy. Methods Narrative synthesis of evidence across hormone-sensitive and castration-resistant settings, interpreted alongside translational data on androgen signaling, PSMA regulation, metabolic stress, DNA-repair competence, and dosimetry principles. Results In hormone-sensitive disease, PSMA induction after androgen suppression may be transient and heterogeneous, and survival endpoints may remain immature, limiting inference on overall survival and increasing susceptibility to design confounders. In contrast, castration-resistant disease more often exhibits stable high-intensity PSMA expression with impaired DNA repair under metabolic stress, conditions that amplify beta-emitter lethality. Physical determinants may also differ across states: lower tumor burden and reduced crossfire can blunt macroscopic impact when fixed-activity regimens are applied uniformly. Conclusion A “biologic readiness” framework defined by target stability, radiosensitivity, and delivered dose may better guide Lu-177 deployment than calendar-based sequencing alone. This concept is intended as an integrative, hypothesis-generating framework rather than a definitive mechanistic explanation.