Genomic predictors of response to cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC): A real-world analysis from the PROMISE registry.

Abstract

5066 Background: Cabazitaxel (Cabazi) is an important treatment for refractory mCRPC, but responses are heterogeneous. Homologous recombination repair (HRR) and tumor suppressor gene (TSG alterations (alt) can predict aggressive behavior in patients (pts) with mCRPC. We hypothesize that Cabazi has enhanced efficacy in pts with these aggressive alt. Methods: The multi-institutional PROMISE clinical-genomic database was queried for patients who had undergone tumor next-generation sequencing prior to initiating Cabazi monotherapy for mCRPC. We evaluated the association of select gene alt HRR ( BRCA1, BRCA2, ATM, BRIP1, CDK12, CHEK2, PALB2, RAD51, RAD51B/CD ), TSG ( RB1 , PTEN loss, TP53 ) and other common alt in mCRPC with PSA response and clinical Progression to Cabazi. Comparisons of PSA50 responses were made using Fisher’s exact tests, and associations between genetic alterations and both OS and PFS were conducted using log-rank tests. Results: Among 383 pts who met inclusion criteria median age was 61 years, with 283 (74%) Caucasian pts, 71 (19%) African-American/Black pts, 9 (2%) Asian pts, and 20 (5%) Hispanic pts. 302 (79%) had prior docetaxel, 23 (6%) had received PARP inhibitor, and 16 (4%) had received Lu-177 PSMA. The most frequent alt noted were: TSG in 204 (53%) pts, TP53 in 164 (43%), AR alt in 130 (34%) pts, and HRR alt in 91 (24%) pts. No significant difference was noted in PSA50 responses in pts with TSG or HRR alt relative to wild-type, though there was a difference noted in pts with PIK3CA alt (Table). Progression-free survival (PFS) on Cabazi was shorter in pts with TP53 alt [HR 1.55 (1.19 – 2.04), p=0.001), any TSG alt [HR 1.51 (1.15 – 1.98) p=0.003], RB1 [HR 2.34 (1.38 – 3.99), p-=0.005], and AR alt [HR 1.37 (1.04 – 1.79) p=0.03). There was no difference in pts with HRR alt [HR 0.83 (0.60 – 1.15), p=0.26)]. Overall survival (OS) was prolonged in pts with HRR alt [HR 0.69 (0.59 – 0.92), p=0.009)] and worse in pts with TP53 alt [HR 1.54 (1.20 – 1.98) p<0.001)], any TSG alt [HR 1.36 (1.07 – 1.74), p=0.01], or RB1 alt [HR 1.94 (1.18 – 3.18) p=0.02]. Conclusions: Common genomic alt including TSG, HRR, and PI3KA were not predictive of Cabazi response in mCRPC. TSG alt were associated with worse outcomes, consistent with aggressive disease biology. Improved OS in pts with HRR alt likely reflects PARP inhibitor or platinum use rather than Cabazi efficacy. Association between genomic alterations and cabazitaxel response in mCRPC. Genetic Alteration PSA50 Response PFS (HR) OS (HR) Any TSG 26.8% vs 25.4%(p=0.80) 1.51 (p=0.003) 1.36 (p=0.01) AR 20.8% vs. 28.6%(p=0.16) 1.37 (p=0.03) 1.19(p=0.19) Any HRR 31.8% vs. 24.6%(p=0.27) 0.83(p=0.26) 0.69 (p=0.009) PTEN 35.7% vs. 24.0%(p=0.09) 1.12(p=0.50) 0.98(p=0.92) PIK3CA 5.6% vs. 27.4% (p=0.05) 1.53(p = 0.22) 1.27(p = 0.36)