Circulating Androgen Receptor (Ar) Gene Amplification And Resistance To 177lu-Psma-617 In Patients (Pts) With Metastatic Castration-Resistant Prostate Cancer (Mcrpc): Results Of A Phase Ii Clinical Trial.

3020 Background: Plasma AR gain is associated with poor prognosis in mCRPC pts treated with abiraterone/enzalutamide, however these pts could benefit from docetaxel (Conteduca et al, Eur Urol 2019). In a phase 2 clinical trial with 177Lu-PSMA-617 in mCRPC pts who progressed after standard survival-prolonging treatments, we aimed to determine if plasma AR gene status enable early assessment of 177Lu-PSMA-617 activity for mCRPC. Methods: Between April 2017 and November 2018, 43 mCRPC pts were treated with 177Lu-PSMA-617 in a phase 2 study. Pts younger than 75 years and not heavily pretreated received 5.5 GBq of 177Lu-PSMA-617, while other pts received 4.2 GBq per cycle, for a total of 4-6 cycles, q8 weeks. We determined AR copy number by droplet digital polymerase chain reaction (ddPCR) on pretreatment plasma samples. We evaluated associations between plasma AR amplification and PSA response (≥50% PSA decline from baseline) and imaging response/progression (as measured by bone scan, CT, and PSMA PET/CT). Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95% CI) in order to evaluate the independent relevance of AR status and pts without PSA response and those with early progressive disease defined as treatment interruption occurring within 4 months of the start of 177Lu-PSMA-617. Results: Forty of 43 pts (median age: 72 years, range 54-86) were fully evaluable for this analysis. A PSA response was reported in 15 (37.5%) of the 40 pts, 3 of 15 (20%) with AR gene gain, and 12 of 25 (48%) with no gain (P = 0.080). Early progressive disease was observed in 17 (42.5%) of the 40 pts, 12 of 15 (80%) with AR gene gain and 5 of 25 (20%) with no gain (P = 0.0002). The OR for pts without PSA response (decline < 50%) having AR gain was 3.69, 95% CI 0.83-16.36, p = 0.085. The OR for pts with early PD having AR gain was 16.00, 95% CI 3.23-79.27, p = 0.0007. The evaluation of germline alterations in DNA damage repair (DDR) genes is ongoing (i.e., BRCA2, BRCA1, ATM). Conclusions: Plasma AR status assessment using ddPCR identifies mCRPC resistant to 177Lu-PSMA-617. These data suggest potential better activity of 177Lu-PSMA-617 in earlier phases of prostate cancer. Prospective evaluation of treatment decision making based on plasma AR status is warranted. Clinical trial information: NCT03454750.