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).

Genitourinary (Prostate) Cancer
Session Type and Session Title: 
Poster Highlights Session, Genitourinary (Prostate) Cancer
Abstract Number: 
J Clin Oncol 32:5s, 2014 (suppl; abstr 5020)
Eric Jay Small, Jack Youngren, George Thomas, Susan Olson, Alexandria Toschi, Adam Foye, Joshi J. Alumkal, Matthew Rettig, Martin Edwin Gleave, Christopher P. Evans, Josh Stuart, Charles J. Ryan, Robert Evan Reiter, Kim N. Chi, Primo Lara, Tomasz M. Beer, PCF/SU2C/AACR West Coast Prostate Cancer Dream Team; University of California, San Francisco, San Francisco, CA; Oregon Health & Science University, OHSU Knight Cancer Institute, Portland, OR; Oregon Health & Science University, Portland, OR; UCLA's Jonsson Comprehensive Cancer Center, Los Angeles, CA; Vancouver Prostate Centre, Vancouver, BC, Canada; University of California, Davis, Sacramento, CA; University of California, Santa Cruz, Santa Cruz, CA; University of California San Francisco, San Francisco, CA; University of California, Los Angeles, Los Angeles, CA; BC Cancer Agency, Vancouver Cancer Centre, Vancouver, BC, Canada; University of California, Davis Medical Center, Sacramento, CA

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Abstract Disclosures


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+.