We sought to correlate real-world outcomes on NHT with comprehensive genomic profiling (CGP)-reported alterations, hypothesizing that AR amplification (ARamp) and deleterious genomic alterations (GAs) in BRCA2, PTEN, RB1, TP53 would correlate with worse outcomes on NHT. Abiraterone (n = 242; 61%) and enzalutamide (n = 145; 39%) were most common NHTs. As hypothesized, ARamp correlated with worse TTD (aHR: 3.37 [1.26-9.0]) and OS (aHR: 4.92 [1.47-16.5]). BRCA2 GA correlated with improved OS (aHR: 0.41 [0.21-0.81]), but no differences in TTD (aHR: 1.25 [0.82-1.9]). RB1 GA had trends for worse OS (aHR: 2.0 [0.93-4.28]) and worse TTD (aHR – 1.41 [0.72-2.8]). TP53 GA had worse OS (aHR: 1.47 [1.1-2.0]), but no difference in TTD (aHR: 1.08 [0.85-1.4]),...ARamp is associated with worse TTD and OS in mCRPC pts treated with NHT in real-world. Surprisingly, BRCA2 GA correlated with improved OS but not TTD.

AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel.

Eighty-four mCRPC patients received abiraterone (n = 40) or enzalutamide (n = 44) as first-line therapy. Twelve patients (14.3%) presented AR gain and 30 (35.7%) AR-V7+ at baseline. Median progression-free survival (PFS) and overall survival (OS) were significantly longer in AR-V7- vs AR-V7+ patients (24.3 vs 5.4 months, p < 0.0001; not reached vs 16.2 months, p = 0.0001, respectively)...The AR gain/AR-V7 combined analysis confirmed a strong predictive effect for biomarkers combination vs patients without any AR aberration (PFS 3.8 vs 28 month, respectively; OS 6.1 vs not reached, respectively; p < 0.0001).

AR/enhancer alterations (copy gain, tandem duplication, and point mutation) in cfDNA were strongly predictive of primary resistance to AR-directed therapy (PPV = 100%, Sens. = 89%).

AR amplification and TP53 or RB1 defect were associated with resistance to abiraterone or docetaxel.

pAR gene aberrations in mCRPC patients (pts) may be associated with worse outcome on AA+P/D....There was a significant association for AR gain and shorter rPFS (median 5.7 months [m]:pAR gain vs 23.7 m:pAR normal; HR: 2.78; 95% CI 1.34 - 4.6; p = 0.004) and PFS (median, 4.90m: pAR gain vs 16.2m: pAR normal; HR: 2.28; 95% CI 1.3 - 4; p = 0.004)...

pAR gene aberrations in mCRPC patients (pts) may be associated with worse outcome on AA+P/D....There was a significant association for AR gain and shorter rPFS (median 5.7 months [m]:pAR gain vs 23.7 m:pAR normal; HR: 2.78; 95% CI 1.34 - 4.6; p = 0.004) and PFS (median, 4.90m: pAR gain vs 16.2m: pAR normal; HR: 2.28; 95% CI 1.3 - 4; p = 0.004)...

Patients with AR gain or T878A or L702H before abiraterone (45%) were 4.9 and 7.8 times less likely to have a ≥50 or ≥90% decline in prostate-specific antigen (PSA), respectively, and had a significantly worse overall [hazard ratio (HR), 7.33; 95% confidence interval (CI), 3.51 to 15.34; P = 1.3 × 10(-9)) and progression-free (HR, 3.73; 95% CI, 2.17 to 6.41; P = 5.6 × 10(-7)) survival. Evaluation of plasma AR by next-generation sequencing could identify cancers with primary resistance to abiraterone.

AR amplification and TP53 or RB1 defect were associated with resistance to abiraterone or docetaxel. CDK12 was more frequently altered in our cohort than those in previous reports which mainly focused on Caucasian population. The patients with CDK12 defect showed rapid resistance to abiraterone and limited efficacy of Poly (ADP-ribose) polymerase inhibitors (PARPi). However, these patients seemed to benefit from chemotherapy, especially platinum-based chemotherapy.