Recent Advances Revolutionize Treatment of Metastatic Prostate Cancer

Ravi A Madan; Philip M Arlen

Disclosures

Future Oncol. 2013;9(8):1133-1144. 

In This Article

Hormonal Therapy

Since the breakthrough discovery of Huggins and Hodges in the 1940s establishing the androgen dependence of prostate cancer proliferation, androgen deprivation has been foundational in the management of metastatic prostate cancer.[12] Androgen deprivation can be achieved surgically by orchiectomy; medically by an LHRH agonist, such as leuprolide; or by a combination of a LHRH agonist plus an androgen receptor antagonist (ARA), for example, bicalutamide (Casodex®; AstraZeneca, London, UK), for complete androgen blockade. Despite initial response rates of 80–90%, virtually all men progress to androgen-insensitive disease. When anti-androgen withdrawal fails, one therapeutic option is the use of an alternative ARA as second-line hormonal therapy.[13,14] The first generation of nonsteroidal anti-androgens approved by the US FDA includes flutamide (Eulexin®; Schering-Plough, NJ, USA), bicalutamide and nilutamide (Nilandron®; Sanofi-Aventis, Paris, France). These bind to the androgen receptor (AR) and inhibit the stimulatory action of testosterone and dihydrotestosterone, the primary androgen that stimulates the growth of prostate tissue, including prostate cancer. It is unclear why some patients with castrate levels of testosterone respond to a second ARA after initial progression, but it is presumed that specific anti-androgens interact differently with the AR on prostate cancer cells.[15] Our growing understanding of the function of androgens and ARs has led to the development of new therapeutic agents, some of which target the AR with greater affinity than first-generation ARAs. Others block androgen synthesis not only in the testes and adrenal glands, but also in the tumor. These recent developments (Table 1) have led to the approval of the ARAs abiraterone and enzalutamide, both of which have significantly improved overall survival (OS) compared with placebo in Phase III trials in patients with castration-resistant prostate cancer (CRPC).

Abiraterone

Administered orally, abiraterone irreversibly inhibits the products of the CYP17 gene, including both 17,20 lyase and 17-α-hydroxylase.[16,17] Through this mechanism of action, abiraterone blocks the synthesis of androgens in the tumor, testes and adrenal glands. The toxicity profile of abiraterone depends on the mechanism of action. Inhibition of 17-α-hydroxylase can result in decreased cortisol levels and a compensatory rise in adrenocorticotropic hormone (ACTH) level, which is mediated by a hypothalamic response to partial adrenal inhibition. Increased release of ACTH can cause increased production of adrenal mineralocorticoid, producing both hypertension and hypokalemia. However, when abiraterone is given without concomitant glucocorticoids, patients typically do not experience clinical adrenal insufficiency since cortisol production is preserved. The effects of mineralocorticoid excess can be attenuated by coadministration of prednisone, which reduces ACTH-mediated stimulation of the adrenal glands.

The clinical benefit of abiraterone was first observed in a Phase III trial in men with mCRPC who had received prior docetaxel.[18,19] In this study, 1195 men were randomized 2:1 to receive either abiraterone at 1000 mg/day with oral prednisone two-times 5 mg/day, or a placebo with prednisone as a control. Treatment continued until disease progression. The study was terminated when results of an interim analysis exceeded prespecified criteria. The final analysis of OS was conducted at a median follow-up of 20 months. There was an increase in OS for patients randomized to abiraterone (median: 15.8 months) compared with patients in the placebo arm (median: 11.2 months). Statistically significant improvements were also seen in time to PSA progression (8.5 vs 6.6 months), radiologic progression-free survival (5.6 vs 3.3 months) and PSA response rate (29.5 vs 6.5%). Secondary analyses focused on the impact of abiraterone on symptoms due to bone metastases.[20] Although there was little difference in skeletal-related events in either study arm, patients in the abiraterone arm had a statistically significant increase in time to development of the first skeletal-related event (25 vs 20 months). Common side effects of abiraterone compared with placebo included fluid retention (33 vs 24%) and hypokalemia (18 vs 9%). Nonspecific cardiac abnormalities (16 vs 12%), abnormal liver function tests (11 vs 9%) and hypertension (11 vs 8%) also appeared to be more common in patients treated with abiraterone.[18,19]

Recent data from a second Phase III study of abiraterone also demonstrate delayed disease progression and improved OS in men with CRPC who have not received prior chemotherapy.[21] In this study, 1088 men with asymptomatic or minimally symptomatic mCRPC were randomly assigned to abiraterone plus prednisone or placebo plus prednisone. The primary end points of this study were OS and radiographic progression-free survival. The results show that median OS has not been reached in the abiraterone arm compared with 27.2 months in the placebo arm (hazard ratio [HR]: 0.75; p = 0.01). In addition, median radiographic time-to-progression (TTP) favored the abiraterone arm, at 16.5 months compared with 8.3 months in the placebo arm. (HR: 0.53; p < 0.001). The FDA has approved abiraterone for use in this population based on this data.[101]

Enzalutamide

Enzalutamide, an orally administered agent, acts at multiple sites in the AR signaling pathway, including blocking the binding of androgen to the AR. In addition to binding to the AR with greater affinity than standard ARAs, enzalutamide prevents downstream effects, including nuclear translocation, DNA binding and signaling to coactivators.[22] Unlike first-generation ARAs, which demonstrated agonist properties in approximately 15–20% of patients,[23,24] enzalutamide does not produce this negative effect. Furthermore, unlike abiraterone, enzalutamide does not require the addition of daily steroids. Initial studies with enzalutamide demonstrated significant activity in men with CRPC.[25]

The AFFIRM trial, a pivotal Phase III study of enzalutamide, randomized 1199 patients with mCRPC, the majority of whom had received numerous prior hormonal- and docetaxel-based chemotherapy regimens. Concurrent therapy with steroids was permitted but not required on both treatment arms. Patients were randomized 2:1 to receive either a single daily dose of 160-mg enzalutamide, or placebo.[26] Patients randomized to the placebo arm were allowed to receive enzalutamide at time of progression. The study demonstrated significantly increased OS in the enzalutamide arm compared with placebo (18.4 vs 13.6 months). Over half of patients randomized to receive enzalutamide had a >50% decline in serum PSA levels. Other clinical benefits in the enzalutamide arm consisted of fewer soft tissue lesions, prolonged PSA progression and prolonged time to first skeletal-related events. Toxicities were relatively minor; however, seven patients in the enzalutamide arm had new onset of seizures compared with none in the placebo arm. Based on these data, the FDA-approved enzalutamide for mCRPC after docetaxel therapy in August 2012.[102]

As with older ARAs, enzalutamide will probably be used to treat early-stage prostate cancer. The minimal side effects of enzalutamide in patients with advanced disease will make it an attractive option for chemotherapy-naive mCRPC and even non-metastatic disease, supplanting the use of older ARAs, such as bicalutamide, which are commonly used in non-metastatic disease.[27] A second Phase III trial (PREVAIL) comparing enzalutamide with placebo in chemotherapy-naive patients with asymptomatic or minimally symptomatic mCRPC has completed accrual and is awaiting final data analysis.[103]

TAK-700

Other agents that inhibit CYP17 are in clinical trials, the most advanced of which is a study of TAK-700 (orteronel), a selective oral 17,20 lyase inhibitor. TAK-700 is currently being compared with a placebo in two multicenter Phase III trials in chemotherapy-naive patients and patients who have progressed on docetaxel.[104,105] In a recent Phase II study (n = 39), TAK-700 was administered without prednisone in patients with non-metastatic CRPC and rising PSA levels, a stage of prostate cancer for which there is no standard treatment. To be able to treat these patients at high risk for metastases and death from their disease with an effective therapy that does not require additional steroids would be a significant advance. The primary objective of this Phase II study was to determine the percentage of patients who achieved a PSA reduction to ≤0.2 ng/ml. Secondary objectives included the safety profile of TAK-700, PSA response rates, time to PSA progression, time to metastasis and duration of progression-free survival. Results of this study were presented at the 2012 ASCO Annual Meeting. Twelve patients achieved a PSA level of ≤0.2 ng/ml as their best response, 23 had a decline in PSA of ≥90% as their best response, and median time to PSA progression was 9 months. The most common adverse events were fatigue (62%), diarrhea (38%) and hypertension (38%).[28]

ARN-509

ARN-509 is an ARA with a mechanism of action similar to enzalutamide. It is a novel second-generation ARA targeted to treat CRPC where first-generation ARAs have failed. ARN-509 was discovered through a screening for compounds with anti-androgenic activity in CRPC, using prostate cancer cells rendered castration-resistant via AR overexpression. The screen, developed by Sawyers and Jung, yielded ARN-509, which initially demonstrated strong anti-tumor activity in mouse models of CRPC.[27] ARN-509 inhibits both AR nuclear translocation and AR binding to androgen response elements in DNA.[29] In contrast to the first-generation anti-androgen bicalutamide, it exhibits no agonist activity in prostate cancer cells that overexpress AR. Its oral bioavailability and long half-life allow for once-daily oral dosing. In addition, it has an excellent preclinical safety profile that makes it a candidate for either a single or combination therapy in various prostate cancer disease states. ARN-509 is currently in the Phase II portion of a Phase I/II clinical trial being conducted at Memorial Sloan–Kettering Cancer Center (NY, USA) and various other institutions across the USA. The open-label study will determine ARN-509's anti-tumor activity, safety and tolerability in patients with advanced CRPC.[106]

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