Intermediate Atypical Carcinoma: Novel Histologic Subtype of mCRPC in Patients Resistant to Androgen Receptor Agonists CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting* May 29 - June 2, 2015 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene Corporation, Genentech, Incyte, and Novartis.

Androgen Receptor–Targeted Agents for Prostate Cancer Agents that target androgen receptor have revolutionized treatment of CRPC Abiraterone: reduces ligand production Enzalutamide: binds and blocks receptor However, development of resistance is near-universal and progressive disease frequently leads to death Limited utility of sequential use of androgen receptor– targeted agents Small cell/neuroendocrine prostate cancer development is being observed CRPC, castration-resistant prostate cancer. Small EJ, et al. ASCO 2015. Abstract 5003.

West Coast Prostate Cancer Dream Team Project and Trial Design Consortium of 6 academic medical centers, sought to identify adaptive pathways in metastatic abiraterone- and enzalutamide-resistant prostate cancer Every-3-Mo Clinical Assessment Guided Biopsy Radiology Optional Biopsy at Progression Metastatic CRPC Amenable to biopsy Progressive Disease: After novel AR targeted rx “Aggressive phenotype” On a WCDT trial Treatment(s) AR, androgen receptor; BL, baseline; CRPC, castration-resistant prostate cancer; CTCs, circulating tumor cells; rx, prescription; WCDT, West Coast Dream Team. N = 300 Serum, plasma, and blood for CTCs collected at baseline, 3 mos after therapy begins, and at progression Small EJ, et al. ASCO 2015. Abstract 5003. Reprinted with permission.

Baseline Characteristics Characteristics, n (%) Patients (N = 100) Gleason score at diagnosis < 8 ≥ 8 53 (42) 72 (58) Previous treatment for mCRPC Abiraterone Enzalutamide Both Neither 54 (40) 13 (10) 23 (17) 45 (33) Metastatic sites Liver Other visceral Bone or lymph node only 24 (20) 18 (15) 77 (64) No. of prior therapies for advanced disease ≤ 1 ≥ 2 Unknown 20 (100) 1 (5) 2 (10) Median PSA, ng/mL (range) 52 (0.4-2250) Median ALP, IU/mL (range) Median LDH, IU/mL (range) 92 (20-1079) 204 (116-856) ALP, alkaline phosphatase; LDH, lactate dehydrogenase; mCRPC, metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen. Small EJ, et al. ASCO 2015. Abstract 5003.

Biopsy: Histology Results 1% 3% 2% Histology of 124 Evaluable Biopsies 2% 1% 26% 35% 13% 13% 51% 27% Mixed histology Intermediate atypical carcinoma* Pure adenocarcinoma Pure small cell neuroendocrine cancer Bone (n = 89) Lymph node (n = 47) Liver (n = 22) Lung (n = 2) Adrenal (n = 3) Soft tissue (n = 6) Brain (n = 1) Bladder (n = 3) *Novel subtype of pure cell population distinct from adenocarcinoma and small cell neuroendocrine cancer. Small EJ, et al. ASCO 2015. Abstract 5003. Reprinted with permission.

Intermediate Atypical Carcinoma: Pathology and Survival New, highly reproducible pathologic subtype by histology, according to consensus of 3 independent histologists Distributed across bone, lymph node, and liver tissues No distinct clinical markers identified for this histologic subtype Serum neuroendocrine marker levels similar in IAC and SCNC and higher than that seen in pts with adenocarcinoma Chromogranin A, P = .029 Neuron-specific enylase, P = .001 OS by Histology 1.0 Log-rank P = .041 0.8 0.6 Survival Probability 0.4 Adeno (NR) IAC (11.9 mos) SCNC (6.6 mos) 0.2 2 4 6 8 10 12 14 16 18 20 22 24 Adeno, adenocarcinoma; IAC, intermediate atypical carcinoma; NR, not reached; OS, overall survival; SCNC, small-cell neuroendocrine cancer. Mos Pts with IAC have poor survival, similar to that seen in pts with SCNC and distinct from that seen in pts with adenocarcinoma (P = .041) Small EJ, et al. ASCO 2015. Abstract 5003. Reprinted with permission.

Intermediate Atypical Carcinoma: Genomics In genomic signature analysis, IAC appears as a transitional pattern between SCNC and adenocarcinoma Associated with intermediate expression of genes used as markers to differentiate these 2 tissue types In select 50-gene signatures for each histology type, expression of IAC samples fell between SCNC and adenocarcinoma (P < .001) IAC, intermediate atypical carcinoma; SCNC, small-cell neuroendocrine cancer. Small EJ, et al. ASCO 2015. Abstract 5003.

Intermediate Atypical Carcinoma: Conclusion Intermediate atypical carcinoma is a new histologic subtype of metastatic CRPC IAC is an aggressive cancer with survival similar to SCNC and distinct from adenocarcinoma IAC is found in 25% of all biopsies of metastases from CRPC When combined with SCNC, included in 40% of all samples IAC and SCNC histologies combined are the largest group of abiraterone and enzalutamide therapy–resistant pts CRPC, castration-resistant prostate cancer; IAC, intermediate atypical carcinoma; SCNC, small-cell neuroendocrine cancer. Small EJ, et al. ASCO 2015. Abstract 5003.

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