Agents Targeting the Androgen Pathway
Androgen signaling is a critical and validated therapeutic target in both hormone-sensitive prostate cancer and CRPC. While the utility of androgen-deprivation therapy (ADT) is well-established in androgen-sensitive disease, targeting the androgen pathway remains important in CRPC, based on evidence that these cells continue to rely on androgen synthesis and receptor signaling.[30-34]
GnRH antagonists in hormone-sensitive prostate cancer
ADT has long been the standard of care for patients with androgen-sensitive prostate cancer. Bilateral orchiectomy is considered the gold standard of ADT but is not as widely used as medical therapy for a variety of reasons, including patient preference and the ability to implement intermittent ADT with medical therapy. Gonadotropin-releasing hormone (GnRH) agonists are the most widely used form of ADT. However, a downside of these agents is the initial testosterone surge that can precipitate clinical disease flare and may necessitate the concomitant use of an antiandrogen.
Degarelix (Firmagon) is a GnRH antagonist that has been shown to produce rapid and sustained testosterone suppression without causing an initial testosterone surge. Degarelix was approved by the FDA in 2008 based on a phase III trial of 601 patients who required initial ADT. The results showed that over 95% of the patients treated with degarelix achieved a castration level of testosterone within three days, compared with none of the patients treated with leuprolide (Lupron). An updated analysis revealed a statistically significant decrease in the incidence of PSA recurrence (a secondary endpoint) at one year using degarelix compared with leuprolide . Overall, adverse reactions with degarelix were representative of those commonly seen with ADT: 40% of treated patients experienced injection site reactions, which were overall mild.
Degarelix provides another option for treating patients. It is useful in patients who have an indication for ADT but who are at high risk for prostate cancer–related flare symptoms, such as bone pain, urethral obstruction, or spinal cord compression. The currently available formulation requires an injection every 28 days, which is less convenient for patients than the available formulations of GnRH agonists that can be given less frequently (eg, every three, four, or six months).
Androgen signaling inhibition in CRPC
Despite initial success with ADT, progression to CRPC is inevitable for most patients. However, there is clear evidence that CRPC remains androgen driven through multiple different mechanisms.[30-34] These include increased expression of the androgen receptor (AR), increased activity of the AR through various gene mutations, and up-regulation of steroidogenic enzymes (such as CYP17) that lead to increased androgen production.
CYP17 Inhibitors. Abiraterone is a novel inhibitor of the adrenal enzyme CYP17 (17α-hydroxylase/17,20-lyase), which is involved in the production of androgenic steroids. Results from several recently published phase I and II studies have shown abiraterone’s antitumor effects as reflected by measurable disease responses and prolonged time to PSA progression.[38-41] A recently reported phase III study randomly assigned 1195 patients with CRPC who had failed docetaxel(Drug information on docetaxel)-based therapy to treatment with prednisone(Drug information on prednisone) plus either abiraterone or placebo. The results showed that abiraterone was associated with improvements in overall survival (14.8 months vs 10.9 months; HR, 0.65 [95% CI, 0.54-0.77]; P < .0001) and time to tumor progression (10.2 months vs 6.6 months; HR, 0.58 [95% CI, 0.46-0.73]; P < .0001). Radiographic progression-free survival and PSA response were also significantly improved with abiraterone (5.6 months vs 3.6 months, and 38% vs 10%, respectively). Abiraterone was well tolerated, with the most frequent adverse events being hypertension, hyperkalemia, and fluid retention. Another phase III study is evaluating abiraterone in asymptomatic or minimally symptomatic patients with CRPC who have not received cytotoxic or biologic therapy. Because this agent inhibits the production of both adrenal androgens and corticosteroids, concomitant exogenous steroid administration (eg, prednisone) is required.
Abiraterone was recently approved by the FDA for patients with metastatic CRPC post docetaxel therapy.
Orteronel (TAK-700) is another inhibitor of CYP17 that has been shown to cause powerful and selective suppression of androgen production in animals. Available data suggest no dose-response relationship, and because lower dose levels have no impact on adrenal corticosteroid production, orteronel presents a potential clinical advantage over abiraterone in that exogenous corticosteroids may not be needed; oreteronel may thus be better suited for long-term use. Orteronel is currently undergoing investigation in a variety of settings: a phase II trial is evaluating orteronel in patients with non-metastatic CRPC, and two phase III trials are evaluating its use in patients with metastatic CRPC who are chemotherapy-naïve and who develop progressive disease after docetaxel.[45-47]
Antiandrogens. MDV3100 is an oral androgen antagonist with a higher affinity for the androgen receptor than bicalutamide(Drug information on bicalutamide) (Casodex). It is also a pure antagonist, whereas bicalutamide is a partial agonist. In a recently published phase I/II study of 140 patients with progressive, metastatic CRPC treated with MDV3100, 78 out of 140 (56%) experienced at least a 50% decrease in serum PSA concentration, and 13 out of 59 (22%) experienced a response in measurable soft-tissue disease. Overall, this agent was well tolerated, with fatigue being the most common toxicity. However, the most common adverse event leading to drug discontinuation was seizure, which occurred in 3 out of 53 patients who received doses of MDV3100 above the maximum tolerated dose. An ongoing phase III trial of patients with CRPC who have not been treated with chemotherapy is randomly assigning patients to treatment with MDV3100 or placebo. Another phase III trial is investigating MDV3100 compared to placebo in patients with CRPC who develop progressive disease after receiving docetaxel. These trials will establish the efficacy and safety of this agent.
Although the focus of research involving this class of agents and the CYP17 inhibitors has been on castration-resistant disease, clearly they may play an even more important role in the setting of hormone-sensitive disease. Trials are therefore critically needed to determine their efficacy in this latter setting.