Numerous lines of evidence indicate that persistent AR activation is an important mediator of disease progression in CRPC [3
]. Proposed mechanisms include: AR
gene amplification or overexpression; AR
gene mutation leading to promiscuous ligand/cofactor interaction; enhanced AR signal transduction mediated via coactivators; and endocrine or autocrine activation of the AR, for example, by adrenal androgens or intratumoral production of dihydrotestosterone (DHT). Established AR-directed approaches include AR antagonists, for example, bicalutamide and flutamide, in addition to agents that block the production of AR-activating hormones, for example, ketoconazole (). However, in patients with AR overexpression, traditional AR antagonists have shown agonistic activity toward the AR [5
], which may explain prostate-specific antigen (PSA) decreases that sometimes occur following antiandrogen withdrawal [6
] and the limited additive effects of antiandrogens combined with luteinizing hormone-releasing hormone–based therapies [8
The androgen synthesis pathway and actions of inhibitors.
MDV3100 is a novel orally available AR antagonist with no known agonistic activity that was discovered through compound screening in a cellular model of prostate cancer activated by AR overexpression [9
]. In a phase I/II trial, 140 patients with progressive CRPC were treated with doses in the range of 30–600 mg/day. In the chemotherapy-naïve and postchemotherapy subgroups, respectively, a 50% PSA decline from baseline occurred in 62% and 51%, a partial response (PR) in soft-tissue tumors evaluable by the Response Evaluation Criteria in Solid Tumors (RECIST) was achieved in 36% and 12%, stabilized bone disease at 12 weeks on bone scan occurred in 63% and 51%, and the median time to radiologic progression was not reached and 29 weeks (47 weeks in all patients) [10
]. A randomized, placebo-controlled phase III study of MDV3100 monotherapy versus placebo in patients with docetaxel-pretreated CRPC has completed accrual; a second phase III study of MDV3100 monotherapy versus placebo in chemotherapy-naïve patients with CRPC has recently opened ().
Selected ongoing clinical trials of targeted agents in CRPC
Therapies that decrease androgen production from both endocrine and autocrine sources are also being developed. Abiraterone acetate is a selective and irreversible inhibitor of cytochrome P450 (CYP450)c17, an enzyme involved in androgen synthesis from both adrenal and other sources. Encouraging activity and safety with abiraterone were seen in phase I studies [11
]. In a phase II trial of 47 patients with CRPC with prior docetaxel therapy, 50% PSA declines were achieved with abiraterone in 51% of patients, and among the 30 patients who had RECIST-evaluable tumors, 27% had a PR [13
]. In a phase II study of abiraterone plus prednisone in patients with CRPC and prior chemotherapy failure (n
= 58), 50% PSA declines occurred in 55% of patients who were ketoconazole naïve, versus 30% of those who had received prior ketoconazole, and the median times to PSA progression were 198 days and 99 days, respectively [14
]. Also, in a study of abiraterone plus prednisone in patients without prior chemotherapy or ketoconazole treatment (n
= 33), a 50% PSA decline was achieved by 79% of patients and the median time to PSA progression was 71 weeks [15
]. In a phase III randomized, double-blind, placebo-controlled trial of 1,195 metastatic CRPC patients previously treated with docetaxel, abiraterone plus prednisone led to a longer overall survival time than with treatment with prednisone plus placebo (median overall survival time, 14.8 versus 10.9 months; hazard ratio [HR], 0.65; p
< .0001) [16
]. A second phase III trial of abiraterone in asymptomatic or mildly symptomatic men with metastatic CRPC who had not received prior chemotherapy has completed accrual, with final results pending data maturity ().
TAK-700 is a novel CYP450c17 inhibitor similar to abiraterone. In preliminary data from a phase I/II study in patients with asymptomatic metastatic CRPC, TAK-700 was well tolerated and preliminary evidence of activity was seen, including 50% PSA declines in 12 of 15 patients who received doses ≥300 mg twice daily for ≥3 months [17
Conversion of testosterone to the more potent DHT by 5α-reductase can occur within tumor tissue and is a mechanism for continued AR activation. Dutasteride, a dual-isoform 5α-reductase inhibitor, was evaluated in several phase II trials. In a study of 25 evaluable patients with asymptomatic CRPC, two had a confirmed 50% PSA decline and nine had stable disease (SD) for 2.5–9 months (defined by PSA, RECIST, bone scan, and symptomatic criteria) [18
]. Dutasteride plus ketoconazole and hydrocortisone was also studied in 57 patients with CRPC, resulting in a 50% PSA response in 56% of patients and median time to progression (TTP) of 14.5 months [19
]. If antitumor effects are to be seen with dutasteride, it is likely that a dose >0.5 mg/day used in benign prostatic hypertrophy will be required.
Paradoxically, preclinical studies have shown that testosterone, if given at a high enough dose, caused regression of an androgen-independent prostate cancer cell line [20
]. In a prior phase I trial of exogenous testosterone administered at three times the normal dose to 12 men with CRPC, treatment was well tolerated, and a >50% PSA decline was observed in one patient [21
]. In order to block peripheral conversion to DHT and potentially increase serum testosterone levels and the therapeutic effect, dutasteride was added to high-dose exogenous testosterone and is currently being studied in an ongoing phase II trial.
HE3235, a structurally related synthetic analog of androstenediol, an adrenal androgen, has shown preclinical activity against CRPC cells and xenografts. In preclinical models of LNCaP cell lines exposed to the combination of HE3235 and either DHT or androstenediol, there was greater AR activity and PSA expression. Parodoxically, however, the addition of HE3235 led to inhibition of tumor formation/growth in xenograft studies, likely through inducing a proapoptotic effect on tumor cells [22
]. Phase I studies have determined that HE3235 is well tolerated across a range of doses, and phase II studies are under way [23