The pivotal phase III prostate cancer trial ARMOR 3-SV will be discontinued based on recommendations made by the trial’s independent data monitoring committee (DMC), according to the manufacturer Tokai Pharmaceuticals. The DMC concluded that ARMOR 3-SV would unlikely meet its primary endpoint of demonstrating improved radiographic progression-free survival (PFS) based on its review of all safety and efficacy data. Top-line data from the trial is not expected until next year.
It’s a big setback for the company, which was seeking the right niche for the agent in a crowded prostate cancer treatment market. ARMOR 3-SV compared galeterone with enzalutamide (Xtandi) in patients with treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), particularly in patients whose prostate tumors expressed AR-V7. These truncated ARs are missing the C-terminal end of the AR that contains the ligand-binding domain, which is known as C-terminal loss. AR-V7 is the most common form of C-terminal loss of androgen receptors (ARs), a key target in resistance. This form of AR-V7 is also thought to make patients unlikely to respond to either enzalutamide or abiraterone acetate (Zytiga).
The trial employed a precision medicine approach for selection of patients with the AR-V7 splice variant by using an AR-V7 clinical trial assay developed by Qiagen, a manufacturer of sample and assay technologies for molecular diagnostics.
Tokai said in a statement that the DMC did not cite any safety concerns associated with galeterone in the trial and that it plans to present data from the trial at an unspecified scientific forum once it is available and has been analyzed.
Galeterone is a selective small molecule that disrupts AR signaling by using the same pathways in current second-generation hormonal therapies, abiraterone and enzalutamide, but also utilizes a third mechanism that degrades the androgen receptor on tumor cells. This impairs the function of the AR by decreasing sensitivity to androgen activity and reducing tumor growth.
Two previous trials involving galeterone include the ARMOR 1 trial, a phase I, multicenter, open-label, dose-escalation study conducted in collaboration with the Department of Defense Prostate Cancer Clinical Trials Consortium. It assessed the tolerability, safety, and efficacy of oral galeterone for chemotherapy-naïve patients with CRPC. The primary goals were to find the optimal dose of galeterone with an acceptable safety profile.
The phase II study, ARMOR 2, evaluated a new formulation of galeterone that demonstrated improved bioavailability. ARMOR 2 was split into 2 parts. Part 1 confirmed dose and target patient population; part 2 was an expansion of the dose and patient population selected in part 1. An optional extension dosing followed completion of part 1 or part 2 for eligible patients.
In the cohort of patients who had not received prior treatment with either abiraterone or enzalutamide (n = 60), researchers noted that prostate-specific antigen (PSA) levels declined by greater than 30% in 50 men (83%) treated with galeterone. PSA levels went on to decline by more than 50% in 70% of these patients.1
Tokai said it intends to evaluate its ongoing expansion of the ARMOR 2 trial in patients with mCRPC with acquired resistance to enzalutamide, as well as a planned study in patients who rapidly progress on either enzalutamide or abiraterone acetate.
All patients currently enrolled in the ARMOR 2 and ARMOR 3-SV trials will be allowed to continue on therapy following consultation with their physicians and study investigators, Tokai said. The appropriate health authorities and clinical study investigators are being notified that ARMOR 3-SV is being discontinued, said the company.
1. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01709734