Association of Declining Prostate-specific Antigen Levels with Clinical Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Receiving [¹⁷⁷Lu]Lu-PSMA-617 in the Phase 3 VISION Trial

Background and objective: The prognostic value of declining prostate-specific antigen (PSA) levels is under investigation in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) receiving PSMA-targeted radioligand therapy with [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617). This post hoc analysis of the phase 3 VISION trial aimed to evaluate associations between PSA decline and clinical and patient-reported outcomes in patients receiving ¹⁷⁷Lu-PSMA-617. Methods: Of 831 enrolled patients with PSMA-positive progressive mCRPC treated previously with one or more androgen receptor pathway inhibitors and one to two taxanes, 551 were randomised to ¹⁷⁷Lu-PSMA-617 plus protocol-permitted standard of care (SoC). Radiographic progression-free survival, overall survival, radiographic objective response rate, and patient-reported health-related quality of life (HRQoL) and pain were analysed in subgroups of patients categorised by the magnitude of unconfirmed PSA decline from baseline. Key findings and limitations: Patients randomised to ¹⁷⁷Lu-PSMA-617 with the best PSA declines of ≥0–<50% (96/551 [17%]), ≥50–<90% (152/551 [28%]), and ≥90% (83/551 [15%]) up to and including week 12 had 61%, 72%, and 88% reduced risks of radiographic disease progression or death, and 51%, 70%, and 87% reduced risks of death, respectively, versus those with increased PSA levels (160/551 [29%]), based on hazard ratios in a multivariate Cox proportional hazard model. In patients with greater PSA declines, radiographic responses were more frequent and median time to worsening in HRQoL and pain scores were longer. Conclusions and clinical implications: The magnitude of PSA decline was associated with improvement in clinical and patient-reported outcomes in patients with mCRPC receiving ¹⁷⁷Lu-PSMA-617 plus SoC in VISION. PSA decline therefore appears to have a prognostic value during ¹⁷⁷Lu-PSMA-617 treatment in this population.