Abiraterone acetate associated with durable PSA responses

Treatment may be promising in patients with castration-resistant prostate cancer.

Results of three recently published studies show that abiraterone acetate, alone or in combination with prednisone, lowered PSA scores in patients with castration-resistant prostate cancer, including those previously treated with ketoconazole.

In two of the three studies, all published in The Journal of Clinical Oncology, researchers observed PSA declines of at least 50% in more than half of the patients assigned abiraterone acetate, a selective, irreversible inhibitor of CYP17 activity.

In an accompanying editorial, Anthony W. Tolcher, MD, and Josh Cooper, PhD, of South Texas Accelerated Research Therapeutics, said the results of these studies could challenge the conventional wisdom that patients do not respond to luteinizing hormone-releasing hormone antagonists or surgical castration.

“The unaddressed food effect, efficacy, and dosing issues notwithstanding, the encouraging results in Ryan et al and other studies of abiraterone acetate that demonstrate a high rate of durable PSA responses may change the current medical lexicon used to describe patients that do not respond to [luteinizing hormone-releasing hormone] agonists or surgical castration: Androgen-independent or hormone-refractory prostate cancer is neither androgen independent nor hormone refractory,” they wrote.

In the first study, conducted by Ryan and colleagues, researchers recruited 33 men with chemotherapy-naive progressive castration-resistant prostate cancer into a phase-1 dose-escalation study of abiraterone acetate. Bone metastases were observed in 70% of patients. Three patients (9%) had locally advanced disease without distant metastases, and 18% of patients had visceral involvement.

Nineteen patients (58%) had previously been assigned ketoconazole for a median of 15 months, and 16 showed a 50% or greater decline in PSA on the drug. Fifteen patients discontinued ketoconazole because of disease progression, and four patients discontinued because of toxicity.

Abiraterone acetate was administered orally as a 250-mg tablet in escalating dose cohorts of 250 mg (n=6), 500 mg (n=9), 750 mg (n=6) and 1,000 mg (n=12), with fed and fasted cohorts enrolled at each dose. On day seven, patients were administered a single dose of abiraterone acetate for pharmacokinetic analysis after an overnight fast or 30 minutes after starting an 800- to 1,000-calorie breakfast. After seven days, the drug was administered daily.

At 12 weeks follow-up, 55% of patients had 50% or greater decreases in PSA levels. This was also true in nine of 19 (47%) patients with prior ketoconazole therapy and nine of 14 (64%) patients without prior ketoconazole therapy.

At any time point studied, a maximal PSA decrease of 50% or greater was seen in 58% of patients. Again, this included 10 patients (53%) with prior ketoconazole exposure and nine patients (64%) without. At a dose of 1,000 mg, 58% of patients had a 50% or greater maximal decrease in PSA.

Adverse events on the drug were mostly grade-1 and grade-2 with no dose-limiting toxicities.

In combination with prednisone

In the second study, Danila and colleagues enrolled 58 men with progressive metastatic castration-resistant prostate cancer who experienced treatment failure with docetaxel-based chemotherapy into a phase-2 multicenter study. Twenty-seven patients (47%) had received prior ketoconazole.

All patients were assigned to 1,000 mg daily abiraterone acetate plus 5 mg twice daily prednisone.

At 12 weeks, the overall proportion of patients with a 50% or greater decline in PSA was 36% (95% CI, 24%-48%); it was 26% among patients who received previous ketoconazole.

Median time to PSA progression was 169 days. Again, the most frequently reported adverse events were grade-1 and grade-2.

Phase-2 study

Abiraterone acetate’s antitumor activity was further shown in a multicenter, phase-2 study conducted by Reid and colleagues.

In it, 47 patients who had progressed on luteinizing hormone-releasing hormone agonists were recruited and assigned to 1,000 mg daily oral abiraterone acetate. All patients had received steroid therapy with docetaxel, and 46 patients had previously been assigned to anti-androgens.

Researchers observed a PSA decline of 50% or greater from baseline in 51% of patients at least once during the study; 68% of patients had 30% or greater declines. Seven patients had declines greater than 90%.

Researchers said a second PSA at least four weeks later confirmed these responses in all but three cases with PSA declines of 50% or greater and four cases with PSA declines of 30% or greater. A confirmatory exam was not available for those patients.

Again, median time to PSA progression was 169 days. Patients were on study for a median of 24 weeks; 25.5% of patients were able to remain on study for longer than 48 weeks.

“If confirmed in randomized studies, this substantial increase in time to progression will be very meaningful to patients,” Tolcher and Cooper wrote in their editorial. “Although corticosteroids were not mandated in this phase-2 study, the incidence of hypertension, hypokalemia, and peripheral edema from mineralocorticoid excess was of sufficient frequency to support the routine use of prednisone as recommended by Ryan et al.”

For more information:

• Danila DC. J Clin Oncol. 2010;doi:10.1200/JCO.2009.25.9259.
• Reid AHM. J Clin Oncol. 2010;doi:10.1200/JCO.2009.24.6819.
• Ryan CJ. J Clin Oncol. 2010;doi:10.1200/JCO.2009.24.1281.
• Tolcher AW. J Clin Oncol. 2010;doi:10.1200/JCO.2009.25.3781.