Real-world overall survival (OS) and time to therapy discontinuation (TTD) of patients (pts) with mCRPC treated with second-generation novel hormonal therapies (NHT) associated with tissue-based comprehensive genomic profiling (CGP).
Authors: Graf Ryon , Madison Russell , Gjoerup Ole , Zhong Lei , Morley Samantha , Chopra Sunandini , Comment Leah , Fisher Virginia , Li Gerald , McGregor Kimberly , Schrock Alexa Betzig , Tukachinsky Hanna , Snow Tamara , Cho-Phan Cheryl D. , Swaminathan Akshay , Ross Jeffrey S. , McCusker Margaret Elizabeth , Zurita Amado J. , Venstrom Jeffrey 
Published: March 2021

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Background: Robust biomarkers for personalization of NHT treatment decisions remains an unmet need. Most assessments of candidate biomarkers to predict NHT resistance have been conducted in clinical trials or academic centers, meriting additional validation in diverse community settings. 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. Methods: Following a prespecified analysis plan, pts were selected from Flatiron Health (FH)-Foundation Medicine (FMI) clinico-genomic database (CGDB), a nationwide deidentified electronic health record database linked to FMI CGP. Inclusion criteria: mCRPC diagnosis, treatment in FH network and CGP result between 1/1/11-3/30/20 where tissue collected prior to initiation of first line (1L) or second (2L) NHT (within 180 days for ARamp +/- comparison). A priori power analyses were conducted. Adjusted hazard ratios (aHR) from multivariable Cox proportional hazard models were utilized for TTD and OS comparisons from start of NHT including: GA groups, adjusted for age, line number, practice type, and left truncation. Results: Among 1626 evaluable pts, 397 received 1L (n = 287; 72%) or 2L (n = 110; 28%) NHT with majority treated in community setting (n = 297; 75%). Abiraterone (n = 242; 61%) and enzalutamide (n = 145; 39%) were most common NHTs. Incidence: ARamp (15%) and deleterious GA in TP53 (45%), PTEN (28%), RB1 (3%), and BRCA2 (8%). Cohort was strongly powered to assess TP53 & PTEN, moderately for ARamp & BRCA2, weakly for RB1. 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]), and PTEN GA did not correlate with TTD (aHR: 0.94 [0.72-1.2]) or OS (aHR: 1.01 [0.74-1.38]). Conclusions: ARamp is associated with worse TTD and OS in mCRPC pts treated with NHT in real-world, mostly community practice, consistent with prior academic center studies and trials data. Surprisingly, BRCA2 GA correlated with improved OS but not TTD. RB1 GA were directionally consistent with prior studies but underpowered. This study supports using CGP to inform decisions for escalation of non-NHT treatment use in conjunction with patient goals and predictive CGP biomarkers for other drugs. Additional biomarkers, multivariable models and, NHT vs taxane chemo predictive assessments will be reported at symposium.