Updated interim results from the ongoing ARMOR2 phase II clinical trial of galeterone in castration-resistant prostate cancer patients demonstrated the potential of galeterone to treat CRPC expressing androgen receptor splice variants, including AR-V7, according to researchers.
The presence of AR C-terminal loss generally, and AR-V7 specifically, has been linked to poor responsiveness to hormonal agents commonly used to treat CRPC.
The data were presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.
“Recent data have shown that the AR-V7 splice variant of the androgen receptor can be a predictor of resistance to treatment with enzalutamide and abiraterone,” said Mary-Ellen Taplin, associate professor of medicine, director of Genitourinary Clinical Research at the Dana-Farber Cancer Institute and Harvard Medical School. “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.”
Consistent with a prior interim analysis, among 39 treatment naïve metastatic CRPC patients, 85 percent achieved a maximal reduction in PSA levels of at least 30 percent (PSA30) and 77 percent achieved a maximal reduction in PSA levels of at least 50 percent (PSA50). Among 60 combined non-metastatic and metastatic treatment naïve CRPC patients, 83 percent achieved a PSA30 and 70 percent achieved a PSA50.
In the second part of the ARMOR2 trial, circulating tumor cells were characterized for the presence of AR C-terminal loss. Seven treatment-naïve CRPC patients have been identified as having C-terminal loss in a retrospective subset analysis; six of these patients had maximal reductions in PSA levels of at least 50 percent.
The seventh patient, who did not show any PSA reduction, discontinued therapy due to an adverse event unrelated to galeterone after approximately six weeks in the trial and did not receive the full 12 week treatment regimen.
As of the data cutoff, the median time to PSA progression among the seven patients is 7.3 months, as defined by the Prostate Cancer Working Group 2 criteria.
Of the six responders with AR C-terminal loss, four elected to continue into an optional extension phase of the trial following the initial 12 week treatment period. The time on treatment for these patients in the extension phase ranged from 155 days to more than 334 days as of the data cutoff.
“In the 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 in independent clinical studies of those compounds,” Taplin said.
Based on the results demonstrated in ARMOR2 in patients with AR C-terminal loss and positive preclinical data in multiple AR-V7 models, Tokai Pharmaceuticals Inc., galeterone’s sponsor, expects to initiate ARMOR3-SV, an open-label phase III registrational trial in the first half of 2015.
In ARMOR3-SV, patients will be screened and those testing positive for AR-V7 will then be randomized to receive either galeterone or enzalutamide. The trial will have a primary endpoint of radiographic progression-free survival, with secondary endpoints that include overall survival, skeletal-related events and time to cytotoxic therapy.
Galeterone is an oral small molecule being developed for the treatment of CRPC that acts by actively disrupting AR signaling via multiple mechanisms of action.
Galeterone combines the mechanisms of action of CYP17 inhibition and androgen receptor antagonism with an additional mechanism of androgen receptor degradation.
