Circulating androgen receptor gene amplification and resistance to 177 Lu-PSMA-617 in metastatic castration-resistant prostate cancer: results of a Phase 2 trial

Background In a Phase 2 clinical trial, we aimed to determine the lutetium-177 [ 177 Lu]-PSMA-617 activity and the clinical utility of levels of plasma androgen receptor (AR) gene in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Methods We determined AR copy number in pretreatment plasma samples. We used logistic regression to estimate the odds ratio (OR) and 95% confidence intervals (95% CIs) in order to evaluate the independent relevance of AR status and to evaluate patients with early progressive disease (PD) defined as treatment interruption occurring within 4 months after the start of 177 Lu-PSMA-617. Results Twelve of the 15 (80%) with AR gene gain and 5 of the 25 (20%) patients with no gain of AR had early PD ( p = 0.0002). The OR for patients without PSA response having AR gain was 3.69 (95% CI 0.83–16.36, p = 0.085). The OR for patients with early PD having AR gain was 16.00, (95% CI 3.23–79.27, p = 0.0007). Overall, median PFS and OS were 7.5 and 12.4 months, respectively. AR -gained had a significant shorter OS compared to AR -normal patients (7.4 vs 19.1 months, p = 0.020). No treatment interruptions due to adverse effects were reported. Discussion Plasma AR status helped to indicate mCRPC with early resistance to 177 Lu-PSMA-617. Trial registration NCT03454750.