Galeterone (Gal) is an oral agent that disrupts AR signaling via AR degradation, CYP17 lyase inhibition, and AR antagonism. In this randomized, open-label, multicenter phase 3 study (NCT02438007), Gal was tested against Enza in men who were found to be AR-V7 positive on pre-treatment circulating-tumor cells (CTCs). This was based on prior phase II demonstrating PSA response in CRPC and ARV7+ CRPC men treated with Galaterone.2 Men who were AR-V7 + were randomized 1:1 to either Gal or Enza. rPFS (by independent blinded central review) was the primary endpoint.
A key part of the presentation revolved around testing of the patients. The testing was done in 3 steps – CTC isolation, mRNA isolation/cDNA generation, PCR amplication of AR and ARV-7. From the time of blood collection, the turnaround time was 3 days for the results to come back.
In the screening process, 953 patients were screened globally for AR-V7 from Sept 2015 through study closure. Of these, 73 men (8%; 95% CI 6-10%) were AR-V7+, 250 (26%) AR-V7–. More importantly, 630 (66%) had no CTCs/AR present (unevaluable). An emphasis on the low yield of this particular test was made throughout the presentation and the subsequent discussion.
AR-V7 detection was better detected in patients with more aggressive disease: higher PSA levels, more bone metastases, presence of M1 disease at diagnosis (dx), shorter time from dx to screening, higher ECOG, prior antiandrogen use and prior docetaxel use.
Moving forward, 38 were randomized (19 Gal, 19 Enz), 31 screen failed, and 4 were discontinued from screening at study halt. Baseline characteristics were balanced among the 38 randomized.
Ultimately, due to the recommendations of the data safety monitoring board (DSMB), the study was closed early as it was unlikely to meet its endpoint. At the time of DSMC meeting, 12 patients had discontinued protocol therapy, and 7 were transitioned rapidly to chemotherapy for significant clinical failure (bone marrow suppression, spinal cord compression). Only 5 patients had qualified events that could be used for analysis. They attributed this high dropout rate and clinical progression primarily due to the advanced disease of patients at the time of inclusion. At the time of the study closure, in the Gal and Enz arms respectively, median time on therapy was 2.0 vs 2.8 mo, median time to PSA progression (PCWG1) was 3.9 vs 3.8 mo, PSA50 response rates in evaluable patients were 2/16 (13%) and 8/19 (42%), and there were no new safety signals.
The authors finally conclude that AR-V7 in CTCs selects for a more aggressive patient cohort. The agree that no conclusions regarding Gal can be made. Their final plea is that novel study designs and alternative treatment approaches are urgently needed for AR-V7+ mCRPC patients.
1. With 66% of men not having evaluable CTC’s, the generalizability of this cohort is slightly limited. The methods of CTC evaluation needs to be further improved prior to making any generalizations regarding treatment decision.
2. This study failed to accrue enough patients to meet its endpoints. As such, it is not powered to make any strong statements regarding either treatment arm.
1. Novel study designs are required for mCRPC patient populations.
2. Improvement in the CTC evaluation is needed to better help characterize patients and thereby improve accrual.
3. No comment regarding Gal efficacy can be made at this time.
Presented By: Gerhardt Attard
Co-Authors: Michael Borre, Howard Gurney, Yohann Loriot, Corina Andresen, Ranjith Kalleda, Trinh Pham, Mary-Ellen Taplin
Institution(s): The Institute of Cancer Research and The Royal Marsden Hospital, Sutton, United Kingdom; Aarhus University Hospital, Aarhus, Denmark; Macquarie University Hospital, Sydney, Australia; Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France; Medivation, Inc., San Francisco, CA; Dana-Farber Cancer Institute, Boston, MA
Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA
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2. Montgomery B, et al. Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer. Clin Cancer Res. 2016 Mar 15;22(6):1356-63. doi: 10.1158/1078-0432.CCR-15-1432. Epub 2015 Nov 2.