The prior discussion in this review has focused on drugs that block androgen signaling via competition for binding to the androgen receptor. However, agents that target the androgen signaling axis in CRPC by interfering with androgen biosynthesis have also met with recent success in clinical trials.
The testis is not the sole source of androgens, borne out by the fact that ADT through surgical castration or treatment with GnRH agonists does not completely eliminate serum or intratumoral androgens. ADT reduces serum testosterone from a normal range of >200 ng/ml to ~10 ng/ml; however, ADT does not affect levels of adrenal androgens such as dehydroepiandrosterone (DHEA) (, ). The remaining androgens are synthesized by the adrenal gland, and complete inhibition of adrenal gland function decreases serum testosterone and adrenal androgens to undetectable levels.
An additional source of androgens may be the tumors themselves. Expression profiling studies found that multiple enzymes involved in steroid synthesis are upregulated in CRPC compared to localized prostate cancer () (4
). Significant gene upregulation was observed for the CYP17 that converts progestins to androgens, for 17 keto-reductase enzyme which converts the weakly potent adrenal androgen androstenedione to testosterone, and for 5α-reductase 1 (SRD5A1), which converts testosterone into the potent androgen dihydrotestosterone (DHT). In addition, CRPC specimens isolated from men on ADT contain higher levels of intratumoral testosterone than primary prostate tumors of untreated men, even though the latter group has higher circulating testosterone levels. Similarly, in a mouse xenograft model, CRPC tumors grown in castrate mice maintained similar intratumoral testosterone levels to those measured in hormone sensitive tumors grown in intact mice (4
There is evidence going back to the 1950s that suppression of adrenal androgen biosynthesis is effective in patients with CRPC. Hypophysectomy to abrogate ACTH-mediated stimulation of the adrenals, and bilateral adrenalectomy both induce clinical responses in up to 50% of patients with disease progression following surgical castration (53
). Given the morbidity and mortality rates of these procedures, pharmacological agents that inhibit androgen biosynthesis have been attractive targets. In addition to the adrenal gland, such agents should also inhibit any intratumoral androgen synthesis.
First Generation Androgen Synthesis Inhibitors
Glucocorticoids inhibit CRH and ACTH secretion via a negative feedback mechanism (), thereby decreasing production of adrenal androgens. Prednisone and hydrocortisone lower serum testosterone and adrenal androgen levels, displaying modest efficacy in CRPC (20
) and in addition, reducing pain and raising energy levels. Currently, glucocorticoids are commonly administered adjunct to chemotherapy in CRPC.
Aminoglutethimide (AGT, Cytadren®
) was initially discovered as an aromatase inhibitor but blocks multiple cytochrome P450 enzymes involved in adrenal corticosteroid synthesis. AGT was studied in several phase II trials in CRPC. While serum levels of the adrenal androgen dehydroepiandrostenedione (DHEA) was suppressed, neither mean testosterone nor mean DHT levels were significantly changed and remained at ~10 ng/dL and 7 ng/dL respectively (). In addition, when compared to hydrocortisone alone, addition of AGT does not further decrease adrenal androgen levels. Approximately 25-50% of patients are reported to have attained stable disease, although the duration of therapy was short (55
Ketoconazole, an imidazole antifungal agent, is another non-specific inhibitor of P450 enzymes. In the phase III CALGB 9583 trial, comparing AAWD (60% bicalutamide, 35% flutamide, 5% nilutamide) with AAWD plus ketoconazole and hydrocortisone, the PSA declines of > 50% rates were 11% and 27%, respectively. However, there was no statistically significant difference in overall survival (57
). As seen with AGT, ketoconazole significantly decreased serum levels of the adrenal androgens DHEA and androsteinedione by ~50%; however, it did not significantly affect testosterone levels. Surprisingly, a rebound of adrenal androgen levels occurs upon disease progression, as compared to the levels after just 1 month of treatment, indicating tachyphylaxis to ketoconazole inhibition (57
). These non-selective p450 enzyme inhibitors have significant dose limiting toxicities including fatigue, neurotoxicity, hepatotoxicity and nausea, limiting quality of life and treatment duration. Additional complications can arise from interference of these agents with the metabolism of multiple drugs.
CYP17 is a key enzyme in the androgen biosynthesis pathway that functions in the testes and adrenal glands to catalyze the respective conversion of pregnenolone and progesterone into the weak androgens DHEA and androstenedione (). These weak androgens are further converted into testosterone and DHT, a process that may occur in peripheral tissues, including prostate cancer tumors.
Abiraterone is a pregnenolone derivative that is a selective, high affinity (IC50
=2 nM), irreversible inhibitor of CYP17 (). Oral Abiraterone acetate was developed to improve oral bioavailability, and undergoes rapid deacetylation in serum. Preclinical studies in intact mice showed that abiraterone acetate treatment at tolerable doses lowered serum testosterone concentrations to castrate levels without significantly affecting serum hydrocortisone levels, whereas ketoconazole treatment suppressed hydrocortisone production more than testosterone production (58
). Abiraterone acetate was initially developed as an oral alternative to GnRH agonists. However, when administered as a single agent, testosterone levels partially recover due to a feedback increase in GnRH levels. Importantly, addition of abiraterone to GnRH treatment results in a substantial decrease in both testosterone and adrenal androgen levels (59
In a dose-finding phase I trial of abiraterone acetate in patients with CRPC, serum levels of testosterone, DHEA, and androstenedione dropped from their respective pretreatment levels of 7ng/dL, 280 ng/dL and 34 ng/dL, to <1 ng/dL, 84 ng/dL, and <2 ng/dL, respectively. This decrease was sustained for more than 4 months of treatment and there was no evidence of tachyphylaxis. Thus, not only is the suppression of andrenal androgens by abiraterone more profound than that obtained with ketoconazole or AGT, but also abiraterone is the first drug that significantly suppresses testosterone levels. Because there were no grade III or IV toxicities, the phase II dose of 1000 mg per day was selected, based on maximal androgen inhibition (60
Extensive phase I and phase II experience with abiraterone in CRPC has now been accumulated. Separate phase II trials were conducted in chemotherapy-naïve and post-chemotherapy CRPC patients (). The drug is very well tolerated. The most recent data from treatment of >100 chemotherapy-naïve patients and >100 post-chemotherapy patients, reported at the 2009 ASCO Genitourinary Cancers Conference, showed significant efficacy with PSA declines of 50% or more in chemotherapy-naïve and ~40% in post-chemotherapy patients. The medium time to progression in these two patient groups was 8 and 5.5 months, respectively (48
). This data has led to an ongoing multinational phase III trial of abiraterone vs placebo with a primary endpoint of overall survival, randomized in a 2:1 manner and targeted to accrue almost 1200 patients whose disease has progressed after docetaxel-based chemotherapy.
Despite promising therapeutic activity, most patients treated on the phase I/II abiraterone trials have progressed. As with other therapies, the progression usually corresponds to an increase in serum PSA levels, suggesting reactivation of AR. One possible mechanism for AR reactivation is the expression of a truncated, constitutively active form of AR, as discussed in the previous section. In addition, abiraterone treatment results in a significant increase in concentrations of steroidal compounds in the biosynthetic pathway upstream of the CYP17 blockade – these include corticosterone, aldosterone and progesterone. These steroids have been shown to activate certain AR mutant proteins isolated in CRPC and AR mutation thus may represent another mechanism for escape. In fact, during the phase I portion of the trial, the addition of 0.5 mg/dL dexamethasone to suppress ACTH mediated stimulation of the adrenal glands resulted in a clinical response in 4 of 15 patients with disease progression while on abiraterone acetate alone. We have observed a similar salvage response in a patient progressing on abiraterone alone where spironolactone was given as a diuretic after withdrawal of spironolactone. Indeed, given its steroidal backbone and structural similarity to progesterone, it would not be unexpected if abiraterone emerged as an AR agonist in certain subsets of CRPC (). In fact, a structurally similar compound, VN/124-1, binds AR with high affinity (see below). Nevertheless, an abiraterone withdrawal response has not yet been reported.
Novel CYP17 inhibitors
A number of groups have developed novel inhibitors of CYP17, but none have yet reached clinical testing. Given the excellent potency and specificity of abiraterone, novel agents would likely require mechanism-based advantages. One such compound may be the steroid VN/124-1 (3β-hydroxy-17-[1H-benzimidazole-1-yl]androsta-5,16-diene). In addition to inhibition of CYP17, VN/124-1 binds and inhibits AR with 10-fold increased affinity compared to bicalutamide. Upon binding, it causes degradation of AR in both cell lines and xenograft models (63
). Given the possible disadvantage of the steroidal structure of both abiraterone and VN/124-1, several groups have developed nonsteroidal CYP17 inhibitors. After several iterations, agents have been synthesized with potencies and pharmacological properties comparable to aberaterone (64
5α Reductase Inhibitors
Testosterone in peripheral androgen dependent tissues is converted to the more potent DHT by two isoforms of 5α-reductase, SRD5A1 and SRD5A2 (, ). SRD5A2 is the predominant isoform in the benign prostate. Finasteride, a specific inhibitor of SRD5A2, lowers PSA levels and reduces prostate weights and has been approved for use in benign prostatic hyperplasia. However, progressive castration resistant prostate cancer is characterized by increased SRD5A1 and decreased SRD5A2 levels(7
). Dutasteride, a potent inhibitor of both SRD5A1 and SRD5A2, inhibits tumor growth in the androgen-sensitive R-3327H rat prostatic adenocarcinoma model and in the probasin large-T antigen (TRAMP) mouse prostate tumor model (66
). In a LNCaP xenograft model, addition of dutasteride but not finasteride treatment to surgical castration, inhibits tumor growth more than the effects of castration alone (67
). In clinical testing, dutasteride has limited activity in CRPC. However, in a phase II trial of combination therapy with ketoconazole, hydrocortisone and dutasteride (KHAD) in 57 patients with CRPC, 30 patients (53%) attained a PSA response and the median time to progression was 13.7 months (68
). How these results compare to abiraterone would require prospective testing.