New Agents for the Management of Castration-Resistant Prostate Cancer

Robert J Cersosimo PharmD BCOP


The Annals of Pharmacotherapy. 2012;46(11):1518-1528. 

In This Article

Abiraterone Acetate

Mechanism of Action

Abiraterone acetate is indicated for use in combination with prednisone for the treatment of patients with metastatic CRPC who have received prior docetaxel-containing chemotherapy.[27] Abiraterone is a structural analogue of pregnenolone and inhibits an enzyme necessary for androgen synthesis, 17α-hydroxylase/C17,20-lyase (CYP17), that is expressed in testicular, prostate, and adrenal tissue. Inhibition of CYP17 results in reduction of androgen synthesis in the testes, adrenal glands, and prostate tissue, resulting in reduced serum levels of testosterone and other androgens.[27,28] Abiraterone is more selective and specific than ketoconazole, which has also been used to treat advanced prostate cancer. Although the activity of abiraterone is primarily confined to effects on androgen production, there is a reactive increase in corticotropin secondary to a pituitary response to the partial adrenal inhibition, which can lead to increased mineralocorticoid production. This can lead to hypokalemia and hypertension, which can be reduced by concurrent prednisone administration.[27,29]


After oral administration, peak plasma concentrations of abiraterone are reached in 1.5–4 hours (mean 2).[27,30] Administration with food increases systemic exposure of abiraterone. The maximum concentration (Cmax) was 7-fold higher after administration with a low-fat meal (7% fat, 300 calories) and 17-fold higher after administration with a high-fat meal (57% fat, 825 calories) when compared to a fasted state. Likewise the AUC was 5-fold higher after the low-fat meal and 10-fold higher after the high-fat meal.[27]

After a dose of 1000 mg the Cmax at steady state was 226 ng/mL and the AUC was 1173 ng·h/mL. Protein binding of abiraterone was >99% and the mean volume of distribution was 19,669 L. Abiraterone acetate is metabolized to abiraterone and exhibits a mean terminal half-life of 12 hours. After administration of 14C-abiraterone acetate, 88% of the dose was eliminated in the feces and 5% in the urine.[27]


Abiraterone is available as 250-mg tablets and is administered at a dose of 1000 mg daily in combination with prednisone 5 mg administered twice daily. Tablets should be taken whole and on an empty stomach, with no food for 2 hours before and 1 hour after administration. The half-life of abiraterone increased to 18 hours in patients with mild hepatic impairment and to 19 hours in those with moderate hepatic impairment. Patients with moderate hepatic dysfunction (Child-Pugh class B) should receive 250 mg daily. The drug has not been studied in patients with severe (Child-Pugh class C) hepatic impairment. If a patient develops hepatotoxicity during treatment, the dose should be withheld until recovery and reinstituted at 750 mg/day. If hepatotoxicity recurs at 750 mg, the dose should be withheld until recovery and reinstituted at 500 mg/day. If hepatotoxicity recurs at 500 mg/day, therapy should be discontinued.[27]

An early study demonstrated that administration of abiraterone alone resulted in a compensatory increase in serum luteinizing hormone levels that overcame the suppressive effect of abiraterone.[31] The manufacturer recommends that LHRH agonists be continued in patients receiving abiraterone and includes this recommendation in their patient counseling information.[27] Most of the patients in the clinical trials had received prior LHRH agonists. Although most trials did not state that LHRH agonists were continued, most of them indicated that serum testosterone levels were maintained at 50 ng/dL or less (Table 3),[10,29,32,33] which was most likely the result of continued LHRH administration. Eligibility criteria for the study included ongoing androgen deprivation therapy and a serum testosterone level of 50 ng/dL or less.[33]

Clinical Activity

Clinical trials of abiraterone are summarized in Table 3.[10,29,32,33] An expansion of the Phase 2 portion of a Phase 1/2 study enrolled 42 men with chemotherapy-naïve CRPC to receive abiraterone at a daily dose of 1000 mg.[32] The primary end point was a 50% or greater PSA decline at any time after 12 weeks of treatment, with a secondary end point of a 30% or greater PSA decline. Measurable target lesions were identified and followed by computed tomography scans. Changes in circulating tumor cell (CTC) counts and median time to PSA progression were also followed.

A 50% or greater PSA decline was seen in 28 patients (67%), while 71% and 19% of patients experienced 30% or greater and 90% or greater declines, respectively. Measurable disease was present in 24 patients, 9 of whom (37.5%) experienced regression consistent with a partial response. Sixteen patients (66%) with measurable disease demonstrated no evidence of progression at 6 months. The median time to PSA progression was 225 days. CTC counts fell from greater than or equal to 5 to less than 5 cells/7.5 mL in 10 of 17 patients, with declines of 30% or greater seen in 12 of 17 patients. Dexamethasone 0.5 mg/day was added to the regimen of patients whose disease progressed on abiraterone. Thirty patients received dexamethasone for 12 or more weeks after progression and 10 (33%) experienced a 50% or greater PSA decline, which the authors interpreted as a reversal of resistance to abiraterone.[32]

A small Phase 2 study administered abiraterone 1000 mg daily to 47 men with CRPC who had received prior docetaxel therapy.[10] The primary end point was a 50% or greater PSA decline in 7 of the first 35 patients, at which point additional patients were enrolled. Secondary end points were a 30% or greater or 90% or greater PSA decline. PSA declines of 30% or greater, 50% or greater, and 90% or greater were seen in 68%, 51%, and 15% of the patients, respectively. Thirty patients had measurable disease, 8 of whom (27%) achieved a partial response. Median time to PSA progression was 24 weeks.

Similar results were reported in another Phase 2 study by the same group, involving 58 men with progressive metastatic CRPC who had received prior docetaxel therapy.[29] These patients received abiraterone 1000 mg daily plus prednisone 5 mg twice daily. The primary outcome was a 50% or greater PSA decline. Additional outcomes included response among those with measurable disease, changes in performance status, time to PSA progression, and changes in CTC count. A 50% or greater PSA decline was reported in 36% of the patients, with 30% or greater declines reported in 47% and 90% or greater declines in 16%. Partial responses were seen in 4/22 patients (18%) and improvement in performance status was identified in 28%. Median time to PSA progression was 24 weeks. Twenty-nine patients had unfavorable CTC counts at baseline, 10 of whom (34%) developed favorable counts after treatment. There were no grade 4 toxicities and the only grade 3 toxicity was fatigue, which occurred in 2% of patients. The most common grade 1–2 toxicities were fatigue (32%), nausea (14%), vomiting (12%), dyspnea (10%), and peripheral edema (9%). The inclusion of prednisone for all patients resulted in much less hypokalemia (5% vs 55%), hypertension (<5% vs 17%), and fluid retention (9% vs 15%) than in the previous Phase 2 trial[10] in which prednisone was not part of the regimen.

This regimen was then employed in a Phase 3 placebo-controlled trial.[33] A total of 1195 patients with progressive disease, prior docetaxel therapy, and ongoing androgen deprivation therapy with a serum testosterone level of 50 ng/dL or less were randomized in a 2:1 ratio to receive prednisone 5 mg twice daily plus either abiraterone 1000 mg daily (n = 797) or placebo (n = 398). The primary end point was overall survival. Secondary end points were time to PSA progression, progression-free survival, and PSA response. The data were unblinded when an interim analysis after a median follow-up of 13 months demonstrated that the outcomes exceeded prespecified results. Median overall survival was significantly longer in the abiraterone group (14.8 vs 10.9 months; p < 0.001). Abiraterone and prednisone produced a 35.4% reduction in the risk of death compared with prednisone plus placebo. All secondary end points were also in favor of the abiraterone group, including PSA response (29% vs 6%; p < 0.001), progression-free survival (5.6 vs 3.6 months; p < 0.001), and time to PSA progression (10.2 vs 6.6 months; p < 0.001).

Abiraterone was used in chemotherapy-naïve CRPC patients in 2 small studies involving a total of 77 patients.[34,35] Both trials evaluated abiraterone 1000 mg daily. In the first trial, 44 patients had received a median of 3 prior hormonal therapies, 70% had bone metastases, and 21 had measurable disease.[34] A 50% or greater PSA decline was reported in more than 60% of patients and the median time to PSA progression was 8.3 months. Twelve of 21 patients with measurable disease (57%) achieved a partial remission.

In the second trial, 33 patients received abiraterone plus prednisone 5 mg twice daily.[35] Patients had received a median of 2 prior hormonal therapies. A 50% or greater PSA decline was reported in 79% of patients and the median time to PSA progression was 16.3 months. Nine of 13 patients with measurable disease (69%) achieved a partial remission. These studies demonstrated that abiraterone has activity in patients with CRPC despite the use of 2 or more prior hormonal therapies.

An interim analysis of the activity of abiraterone in patients with chemotherapy-naïve CRPC was recently reported in a Phase 3 trial.[36] Patients (n = 1088) with asymptomatic or mildly symptomatic metastatic disease were randomly assigned to receive abiraterone (1000 mg/day) plus prednisone (5 mg twice daily) or placebo plus prednisone (5 mg twice daily). The primary end points were radiographic progression-free survival (rPFS) and overall survival. After a median follow-up of 22 months there was a significant improvement in rPFS, which was 8.3 months in the placebo group and had not yet been reached in the abiraterone group (HR 0.43; 95% CI 0.35 to 0.52; p < 0.0001). Median overall survival was 27.2 months in the placebo group and had not been reached in the abiraterone group (HR 0.75; 95% CI 0.61 to 0.93; p = 0.0097). The abiraterone group had significantly better outcomes in the secondary end points of time to chemotherapy initiation (25.2 vs 16.8 months; HR 0.58; 95% CI 0.49 to 0.69; p < 0.0001) and time to PSA progression (11.1 vs 5.6 months; HR 0.49; 95% CI 0.42 to 0.57; p < 0.0001). An independent monitoring committee concluded that all end points favored the abiraterone group and recommended that the study be unblinded and placebo patients crossed over to abiraterone treatment. This was the first randomized study to demonstrate that inhibition of extragonadal androgen synthesis can have a significant survival and rPFS advantage in chemotherapy-naïve patients and can also delay initiation of chemotherapy. This could lead the way to use of abiraterone before chemotherapy.

Adverse Effects

Abiraterone was well tolerated in the Phase 3 trial.[10] The most common adverse effects in the abiraterone and placebo groups, respectively, were fatigue (44% vs 43%), fluid retention and edema (31% vs 22%), back pain (30% vs 33%), nausea (30% vs 32%), arthralgia (27% vs 23%), constipation (26% vs 31%), bone pain (25% vs 28%), anemia (23% vs 26%), vomiting (21% vs 25%), and diarrhea (18% vs 14%). Most of these effects were grade 1–2. The most common grade 3–4 adverse effects in the abiraterone and placebo groups, respectively, were fatigue (9% vs 10%), anemia (7% vs 8%), back pain (7% vs 10%), and bone pain (6% vs 7%).

Adverse effects due to increased mineralocorticoid levels secondary to CYP17 blockade were more common with abiraterone. Specific effects that were significantly higher with abiraterone than placebo included fluid retention and edema (31% vs 22%; p = 0.04) and hypokalemia (17% vs 8%; p < 0.001).[33] Coadministration with a corticosteroid reduces corticotropin influence and the incidence and severity of these reactions. Cardiac events were more common with abiraterone (13% vs 11%; p = 0.14). The most common cardiac effects with abiraterone and placebo, respectively, were tachycardia (3% vs 2%) and atrial fibrillation (2% vs 1%). The incidence of liver function abnormalities was similar between abiraterone and placebo (10% vs 8%, respectively).

A bone scan flare has been described in a small group of patients who received abiraterone for advanced CRPC.[35] Thirty-three patients received abiraterone plus prednisone in a Phase 2 trial. PSA was evaluated at baseline and monthly and bone scans were obtained at baseline and every 3 cycles. A bone scan flare was defined as disease progression as described in a radiologist's report after 3 months of therapy in the face of a 50% or greater PSA decline, which then improved or remained stable 3 months later. Twenty-six patients (79%) achieved a 50% or greater PSA decline, 23 of whom were evaluable for a possible bone scan flare. Twelve of 23 patients (52%) had worse bone scans from baseline at 3 months. At 6 months, 4 of these 12 patients demonstrated improvement and 7 demonstrated stability. The overall incidence of bone scan flare was 48%, seen in 11 of 23 evaluable patients. One patient had a worse scan at 6 months despite a continued PSA decline.