Tokai Pharmaceuticals, Inc.

Metastatic castration resistant prostate cancer is one of the main causes of male cancer associated deaths worldwide. Development of resistance is inevitable in patients treated with anti-androgen therapies. This highlights a need for novel therapeutic strategies that would be aimed upstream of the androgen receptor (AR). Here we report that the novel small molecule anti-androgen, galeterone targets USP12 and USP46, two highly homologous deubiquitinating enzymes that control the AR-AKT-MDM2-P53 signalling pathway. Consequently, galeterone is effective in multiple models of prostate cancer including both castrate resistant and AR-negative prostate cancer. However, we have observed that USP12 and USP46 selectively regulate full length AR protein but not the AR variants. This is the first report of deubiquitinating enzyme targeting as a strategy in prostate cancer treatment which we show to be effective in multiple, currently incurable models of this disease.

Purpose: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study.Experimental Design: In ARMOR1, 49 patients received increasing doses (650–2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700–3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed.Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events.Conclusions: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition. Clin Cancer Res; 22(6); 1356–63. ©2015 AACR.

The fastest growing population in the United States is composed of individuals over the age of 65 years. Prostate cancer (PC) disproportionately affects the elderly, with the highest incidence rates seen in those 70 to 80 years of age.1 Owing in part to the aging population and long natural history of the disease, approximately 54% of men who die of PC are older than 80 years of age.1 Despite the increasing age of the population and increasing cancer incidence, elderly patients are unrepresented in clinical trials. Although 61% of new cancer cases occur in the elderly, this population comprises only 25% of cancer clinical trials participants.2, 3 Elderly patients more frequently experienced delays in treatment and dose reductions related to adverse events compared to younger patients, possibly reducing the efficacy of therapy.4 Additionally, this population is particularly susceptible to toxicity from antineoplastic therapies secondary to age-related changes in pharmacodynamics and pharmacokinetics, polypharmacy, underlying comorbidities, and reduced functional status.5 Men with high-risk localized PC, have significant disease-related morbidity. Data on the natural history of untreated PC indicates that men with high-risk disease over the age of 70 have a 10-year PC-specific mortality of 70%.6 Furthermore, men with castration-resistant prostate cancer (CRPC) have a poor prognosis with fewer than 20% of patients surviving beyond three years.7 Consequently, the optimal management of PC in elderly men, particularly octogenarians and older individuals, poses a unique clinical challenge. It requires the careful assessment of multiple factors, in addition to chronological age. Furthermore, there exists a need for more efficacious therapies with less toxicity for CRPC. Our understanding of androgen receptor (AR) signaling in the pathogenesis of advanced PC has heralded the approval of new therapeutic agents. Abiraterone acetate is an irreversible inhibitor of CYP17, a key enzyme in cortisol and androgen biosynthesis.8 Given abiraterone’s selectivity for 17α-hydroxylase and risk of mineralocorticoid excess, it is administered with prednisone.8 Enzalutamide is a competitive antagonist of the AR, with downstream effects on AR nuclear translocation and association with DNA.9 Despite improvements in survival with these agents, 20–40% of patients have no response to therapy and the majority of patients with an initial response develop secondary resistance.8, 10, 11 Furthermore, cross-resistance is commonly observed when these agents are used in sequence.12, 13 Thus, new therapies are needed to overcome resistance and provide durable responses. Galeterone (TOK-001) is a novel, selective, rationally-designed, semi-synthetic steroid analogue currently under investigation for the treatment of PC. Galeterone inhibits PC growth via: 1) irreversible and selective CYP17,20-lyase inhibition, 2) competitive antagonism of the AR with associated downstream effects on AR-mediated transcription, and 3) AR protein degradation, thus inhibiting androgen signaling within PC cells.14 Galeterone does not require concomitant steroids and has demonstrated a favorable safety profile in phase I/II trials.15, 16 To encourage the inclusion of elderly patients in trials, we describe a nonagenarian with non-metastatic CRPC treated with galeterone in a phase I trial.