Galeterone Shows Activity in Variant Form of Castration-Resistant Prostate Cancer
Results from the ARMOR2 of the anticancer drug galeterone shows that it is successful in lowering prostate-specific antigen (PSA) levels in men with a variant form castration-resistant prostate cancer. The findings, presented at the 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona (Abstract 4), showed that galeterone was well-tolerated and also lowered PSA levels in a subset of patients with castration-resistant prostate cancer that was refractory to enzalutamide (Xtandi) or abiraterone acetate (Zytiga).
“Recent data have shown that a variant of the androgen receptor called AR-V7, found in tumor cells circulating in the blood of patients with metastatic castration-resistant prostate cancer, predicted resistance to treatment with enzalutamide and abiraterone,” reported Mary-Ellen Taplin, MD, Associate Professor at Dana-Farber Cancer Institute, Boston. “Indeed, we believe AR-V7 and other related variants are a mechanism of resistance in this disease and patients who have them may have a poorer prognosis.”
Researchers believed that galeterone could be effective against castration-resistant prostate cancer because it disrupts the androgen receptor signaling pathways that are involved in the cancer, and preclinical work has shown it is active against the AR-V7 variant.
Study Details
This multicenter phase II study recruited four groups of men with castration-resistant prostate cancer to receive 2,550 mg of galeterone orally once a day; 22 men had nonmetastatic castration-resistant prostate cancer and had received no previous treatment, 39 men had metastatic castration-resistant prostate cancer and no previous treatment with abiraterone or enzalutamide, and 37 and 9 men had metastatic castration-resistant prostate cancer that was refractory to abiraterone and enzalutamide treatment, respectively.
As well as evaluating PSA responses to the drug, the researchers also analyzed levels of circulating tumor cells, including identifying whether or not they contained the AR-V7 variant. The AR-V7 variant is formed when an androgen receptor loses the end part of the receptor, called the C-terminal end; this is deleted due to an error in RNA processing in tumour cells, leaving only the beginning part of the receptor, the N-terminal end. The researchers concluded that patients with circulating tumor cells with more N-terminals than C-terminals had the androgen receptor variants.
Meaningful PSA Declines
“We found that galeterone resulted in meaningful PSA declines in patients with metastatic castration-resistant prostate cancer, and imaging showed that the disease was stable or had responded to the drug,” Dr. Taplin said. “Galeterone was safe, without any unexpected toxicity. We also detected circulating tumor cells, which were found in higher numbers in patients who had received more prior therapies.
“In a subset of seven patients who had circulating tumor cells with a higher ratio of N-terminal compared to C-terminal androgen receptors and so were likely to have the AR-V7 variant, six had favorable PSA responses to galeterone. This suggests that the presence of AR-V7 in circulating tumor cells does not preclude response to galeterone as has been shown to be the case for abiraterone and enzalutamide.”
Among the group of men who had nonmetastatic and metastatic disease who had not received prior treatment with abiraterone and enzalutamide, data for 60 were available for analysis. PSA levels declined by 30% or more in 50 out of 60 (83%) patients, of whom 42 (70%) went on to have declines of 50% or more. Among patients who were resistant to abiraterone, 37 were available for evaluation; 13 out of 37 (35%) had any PSA decline. Among patients who were resistant to enzalutamide, nine were evaluable; five out of nine (56%) had any PSA decline.
The presence of circulating tumour cells were evaluated in 71 patients and were found to be higher in 64 (90%) of the patients who had more advanced cancer that had failed more previous treatments.
Next Steps
Galeterone will now be tested in a phase III trial in which patients with metastatic castration-resistant prostate cancer with the AR-V7 variant will be randomly assigned to receive either galeterone or enzalutamide. The researchers will be looking to correlate AR-V7 with response to galeterone and to see what effect the drug has on the length of time patients survive without their disease progressing.
“This phase III trial will be noteworthy for being the first prostate cancer trial to assess a biomarker, namely AR-V7 in circulating tumor cells, as a predictor of response at the same time as testing the efficacy of the drug,” Dr. Taplin concluded.
The study was funded by Tokai Pharmaceutical. For full disclosures of the study authors, view the study abstract at www.ecco-org.eu.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
