In metastatic castration resistant prostate cancer (mCRPC) low serum androgens prior to starting Abiraterone Acetate (AA) is associated with more rapid progression. We evaluated the effect of AA on androgens in CRPC metastases and associations of intratumoral androgens with response.
We performed a phase II study of AA plus prednisone in mCRPC. The primary outcome was tissue testosterone at 4 weeks. Exploratory outcomes were association of steroid levels and genomic alterations with response, and escalating AA to 2000mg at progression.
29 of 30 men were evaluable. Testosterone in metastatic biopsies became undetectable at 4 weeks (p<0.001). Serum and tissue DHEAS remained detectable in many patients and was not increased at progression. Serum and tissue DHEAS in the lowest quartile (pre-treatment), serum DHEAS in the lowest quartile (4 weeks), and undetectable tissue DHEAS (on therapy) associated with rapid progression (20 vs 48 weeks p=0.0018; 20 vs 52 weeks p=0.0003; 14 vs 40 weeks p=0.0001; 20 vs 56 weeks p=0.02, respectively). One of 16 men escalating to 2000mg had a 30% PSA decline; 13 developed radiographic progression by 12 weeks. Among patients with high serum DHEAS at baseline, wild type PTEN status associated with longer response (61 vs 33 weeks; p=0.02).
Low circulating adrenal androgens levels are strongly associated with an androgen-poor tumor microenvironment and with poor response to AA. CRPC patients with higher serum DHEAS levels may benefit from dual-AR pathway inhibition, while those in the lowest quartile may require combinations with non-AR directed therapy.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Aug 18 [Epub ahead of print]
Elahe A Mostaghel, Brett T Marck, Orpheus Kolokythas, Felix Chew, Evan Y Yu, Michael T Schweizer, Heather H Cheng, Philip W Kantoff, Steven P Balk, Mary-Ellen Taplin, Nima Sharifi, Alvin M Matsumoto, Peter S Nelson, R Bruce Montgomery
Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System ., GRECC, V.A. Puget sound., University of Washington., Radiology, University of Washington., Medicine (Oncology), University of Washington and Fred Hutchinson Cancer Research Center., Department of Medicine, Division of Oncology, University of Washington., Medical Oncology, Fred Hutchinson/University of Washington Cancer Consortium., Department of Medicine, Memorial Sloan Kettering Cancer Center., Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center., GU Oncology, Dana-Farber Cancer Institute., Cancer Biology, Cleveland Clinic., Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System., Division of Clinical Research, Fred Hutchinson Cancer Research Center., Medicine, University of Washington.