Biomarker-Directed Galeterone Explored in Prostate Cancer Trial

Mary-Ellen Taplin, MD

Although recent advances in the understanding and treatment of metastatic castration-resistant prostate cancer (mCRPC) are encouraging, the disease remains lethal at this stage because of the resistance to hormonal therapy that develops.¹

One of the important mechanisms of resistance is the prostate cancer cells’ reliance on androgen receptor (AR) signaling. The cells accomplish this by amplifying the AR itself, by upregulating androgens in the tumor so the tumor cells are not dependent on circulating androgens, and by selective growth from mutations in the AR either through point mutations or splice variants. This has established AR as a primary target of therapy, and the focus of ongoing research efforts.¹

Galeterone is a selective small molecule that disrupts AR signaling in several ways. It is distinct from other mCRPC therapies in that it combines inhibition of CYP17 lyase, which hampers androgen synthesis, while blocking androgen binding and employing the novel mechanism of increasing AR protein degradation.

The drug is being explored in the ARMOR 3-SV study,² in which men with progressive metastatic disease who have received prior androgen deprivation therapy are randomized to receive either galeterone or enzalutamide. Entry is restricted to patients with detectable levels of the AR-V7 splice variant in circulating tumor cells (CTCs); AR-V7 is the most common form of C-terminal loss of androgen receptors.³

The study is the first phase III trial of any drug for the treatment of prostate cancer in a specific subset of men carrying a particular biomarker. If the trial is positive, galeterone would become the first biomarker- directed therapy for prostate cancer, Mary-Ellen Taplin, MD, director of Clinical Research, Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, said in an interview.

ARMOR 3-SV Trial¹

Progressive Metastatic Prostate Cancer

CRPC indicates castration-resistance prostate cancer; CTCs, circulating tumor cells; ECOG, Eastern Cooperative Oncology Group.

“Our concept for ARMOR 3-SV was to screen patients for AR-V7 and then randomly assign them to galeterone or standard of care. We are using enzalutamide as standard of care; galeterone will be available in the spray dry dispersion (SDD) tablet formulation,” said Taplin. Taplin is the principal investigator on the ARMOR 3-SV trial and served in the same role for two prior studies.

ARMOR 1 was a phase I, multicenter, open-label, dose-escalation study conducted in collaboration with the Department of Defense Prostate Cancer Clinical Trials Consortium.⁴ 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, said Taplin. The goals were defined as an observed dose-limiting toxicity rate of ≤35%, and to identify a dose for further phase II study.

The phase II study, ARMOR 2, evaluated a new formulation of galeterone that demonstrated improved bioavailability in 144 men.⁵ “In transitioning from ARMOR 1 and ARMOR 2, the drug was reformulated for better absorption and pharmacokinetics,” said Taplin.

ARMOR 2 was split into two 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 galetrone. PSA levels went on to decline by more than 50% in 70% of these patients.⁵

In patients who demonstrated aquired resistance to abiraterone (n = 37), PSA levels declined by any amount in 35% (13 of 37) of patients. Data from 9 patients who were resistant to enzalutamide were also evaluated. In this cohort, PSA levels declined by any amount in 56% (5 of 9) of these patients. The efficacy, safety, and pharmacokinetic results from ARMOR 1 and ARMOR 2 support the recommended dose of galeterone 2550 mg daily, said Taplin. “We had stored circulating tumor cells from some of the ARMOR 2 patients so we were able to look at 7 patients in ARMOR 2 who had CTCs that expressed androgen receptor,” said Taplin. “The AR splice variants were analyed immunohistochemically using the Epic Sciences assay. Galeterone worked fairly well in those patients. So that gave us the rationale to say that galeterone may meet an unmet need in patients who are AR splice variant—positive in the metastatic CRPC setting.”

One thrust of the research is to shut down the pathways that promote the growth of prostate cancer despite treatment. Many patients will have sequential responses to hormone therapy, noted Taplin. “Men will have castrate levels of testosterone in the blood, but the tumor itself will remain hormone responsive. So they may have a second response, then a third response,” she said. “These new drugs under development are not just ‘me too’ drugs. They have different mechanisms of action that lead to the hypothesis that they can work better than the drugs that were approved before them.

Galeterone, with its different mechanism of action, could work in the context of splice variants.” Taplin noted that it wasn’t until investigators started doing biopsies on patients and measuring hormone levels in these tumors that researchers could understand that the blood level of testosterone may be very low, but the tumor level of testosterone could be very high. “Also the androgen receptors are frequently amplified,” she said.

“We have a long way to go, but in the course of the last 5 years, there have been significant improvements for prostate cancer. Drugs like galeterone are trying to raise the bar higher, and this in turn will help more patients," Taplin said.

References

1. Montgomery B, Eisenberger MA, Rettig M, et al. Androgen receptor modulation optimized for response (ARMOR) phase I and II studies: galeterone for the treatment of castration-resistant prostate cancer [published online November 2, 2015]. Clin Cancer Res. doi:10.1158/1078-0432.CCR-15-1432.
2. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT02438007.
3. Tokai Pharmaceuticals. www.tokaipharmaceuticals.com. Accessed February 16, 2016.
4. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT009599959.
5. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT01709734.