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Androgen receptor (AR) amplification in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to therapy with abiraterone acetate or enzalutamide: Preliminary results from the SU2C/PCF/AACR West Coast Prostate Cancer Dream Team (WCDT).
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Background: The mechanisms of resistance to androgen signaling inhibitors such as Abiraterone (Abi) or Enzalutamide (Enz) are poorly understood. AR amplification (AR+) has been observed in Abi/Enz naive mCRPC patients (pts), but its role in Abi/Enz resistant pts is not known. Progressive mCRPC has historically been challenging to biopsy and characterize on a molecular basis because of its bone tropism. As part of the WCDT project which aims to identify genetic pathways underlying primary and acquired resistance to Abi and Enz, AR+ was assessed in mCRPC biopsies. Methods: Following central radiologic review, eligible mCRPC pts underwent biopsy at one of 5 WCDT clinical sites, using a uniform biopsy protocol. Tissue was both frozen, and formalin fixed/paraffin embedded (FFPE). FFPE tissue underwent a CLIA-certified assessment of a mutational panel, IHC for PTEN, and fluorescence in situ hybridization (FISH) for AR+. Results: 60 of 300 planned mCRPC pts have undergone a metastasis biopsy. To date, 33 pts have had biopsies successfully evaluated by AR FISH, including 12 from bone, 11 from lymph nodes, 8 from liver and 2 from other soft tissues. Of 16 Abi and Enz naive pts, 13 (81%) were AR+. By contrast, only 1/11 Abi resistant pts (9%) was AR+. 4/6 Enz resistant pts (67%) were AR+. Of 6 AR+ patients that went on to receive Abi or Enz, 3 (50%) had a response (PCWG2 criteria), whereas of 5 pts without AR+ who went on to receive Abi/Enz, just 1 (20%) had a response. Conclusions: AR amplification can be evaluated by FISH in small biopsies of mCRPC, including bone, and it was observed in 18/33 samples (55%). AR+ was common in mCRPC patients prior to therapy with Abi or Enz (81%). However, once resistance developed, Abi resistant pts had a far lower likelihood of AR+ (9%) than Enz resistant pts (67%). These data support the hypothesis that treatment with Abiraterone selects for non-AR amplified cells, whereas Enzalutamide does not. In this relatively small cohort, mCRPC pts with AR+ are more likely to respond to subsequent AR targeted therapeutics than pts without AR+.
Abstracts by Eric Jay Small:
A multicenter phase I study of cabazitaxel (Cbz), mitoxantrone (Mito), and prednisone (Pred) (CAMP) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC).Meeting: 2015 Genitourinary Cancers Symposium | Abstract No: 238
A multidisciplinary clinic to mitigate the impact of androgen deprivation therapy in prostate cancer: A pilot study.Meeting: 2015 Genitourinary Cancers Symposium | Abstract No: 218
Impact of crossover and baseline prognostic factors on overall survival (OS) with abiraterone acetate (AA) in the COU-AA-302 final analysis.Meeting: 2015 Genitourinary Cancers Symposium | Abstract No: 142