AAP and androgen deprivation therapy (ADT) treatment significantly improved overall survival (OS) and radiological progression-free survival (rPFS) in mCSPC pts with adverse prognostic factors. This analysis was aimed to identify predictive markers associated with response or resistance to AAP to guide combination and subsequent therapies.
DNA (n = 43) and RNA (n = 48) extracted from archived tumor samples from the LATITUDE study were sequenced using next generation and targeted DNA sequencing. Androgen receptor (AR) anomalies (copy number changes and mutations), frequency of DNA repair deficient (DRD: BRCA1/2, ATM, BRIP1, CHEK2, PALB2, FANCA, HDAC2) tumors and other resistant markers were probed. ARV7 expression was assessed in archived tumors (n = 105) by immunohistochemistry. Associations of biomarkers with rPFS and OS were assessed using univariate cox proportional hazards models.
Of 105 treatment-naïve tumor samples tested, none of them met previously defined H-score cut off for ARV7 staining of > 5%, while 4/105 (4%) showed >1% ARV7 staining. A non-synonymous AR mutation (E654K) was detected in one sample (1/43), while none of the samples showed AR amplification. Impact of ARV7 expression on clinical outcomes was inconclusive due to small sample size of positive results. DRD tumors were observed at an overall frequency of 6/42 pts (14.3%: 4 biallelic), 4/30 pts (13.3%; 3 biallelic) in the AAP arm and 2/12 pts (16.7%: 1 biallelic) in control arm. Incidences of BRCA1/2 were only observed in AAP arm at a frequency of 2/30 (6.7%). In the AAP arm, shorter PFS was observed for DRD+ vs DRD– cohort (median 21.01 vs 24.14 mo; HR: 3.9; 95% CI: 1.1-12.1; p = 0.03). Genomic alterations were observed in PTEN (32.5%), TMPRSS2 (30%), TP53 (25.55), SPOP (20.9%) and APC (13.9%) genes, however, associations with clinical outcomes were not meaningful due to fewer samples and events.
AR splice variants and mutations were absent/rare in treatment naïve tumor samples from men with castrate-sensitive prostate cancers. The DRD+ cohort appears to show poorer rPFS outcome in AAP treated men.
NCT01715285.
Shweta Pitre, MPharm, ISMPP CMPP™ (SIRO Clinpharm Pvt. Ltd., India) provided writing assistance and Namit Ghildyal, PhD (Janssen Global Services, LLC) provided additional editorial support.
Janssen Research and Development, LLC.
Janssen Research and Development, LLC.
K.N. Chi: Research grant/Funding (self): Janssen Pharmaceuticals, Astellas Pharma, Amgen, Bayer, Novartis, Sanofi, Exelixis, Tokai Pharmaceuticals, Oncogenex, Teva; Advisory/Consultancy: ESSA, Astellas Pharma, Janssen Pharmaceuticals, Sanofi, Lilly/ImClone, Amgen, Bayer, Takeda Pharmaceuticals; Honoraria (self): Sanofi, Janssen Pharmaceuticals, Astellas Pharma. S. Thomas: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. M. Gormley: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. D. Shen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. S. Joshi: Full/Part-time employment: Janssen Research & Development. N. Tran: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. M. Smith: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. D. Ricci: Shareholder/Stockholder/Stock options, Full/Part-time employment: Janssen Research & Development. K. Fizazi: Advisory/Consultancy, Received personal fees: Amgen; Advisory/Consultancy, Received personal fees: Astellas; Advisory/Consultancy, Received personal fees: AstraZeneca; Advisory/Consultancy, Received personal fees: Bayer; Advisory/Consultancy, Received personal fees: Clovis; Advisory/Consultancy, Received personal fees: Curevac; Advisory / Consultancy, Received personal fees: Essa; Advisory/Consultancy, Received personal fees: Genentech; Advisory/Consultancy, Received personal fees: Janssen; Advisory/Consultancy, Received personal fees: Merck Sharp and Dohme; Advisory/Consultancy, Received personal fees: Orion; Advisory/Consultancy, Received personal fees: Sanofi.