Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate

Abstract

Purpose: The principal objective of this trial was to evaluate the antitumor activity of abiraterone acetate, an oral, specific, irreversible inhibitor of CYP17 in docetaxel-treated patients with castration-resistant prostate cancer (CRPC).

Patients and methods: In this multicenter, two-stage, phase II study, abiraterone acetate 1,000 mg was administered once daily continuously. The primary end point was achievement of a prostate-specific antigen (PSA) decline of > or = 50% in at least seven of 35 patients. Per an attained phase II design, more than 35 patients could be enrolled if the primary end point was met. Secondary objectives included: PSA declines of > or = 30% and > or = 90%; rate of RECIST (Response Evaluation Criteria in Solid Tumors) responses and duration on study; time to PSA progression; safety and tolerability; and circulating tumor cell (CTC) enumeration.

Results: Docetaxel-treated patients with CRPC (N = 47) were enrolled. PSA declines of > or = 30%, > or = 50% and > or = 90% were seen in 68% (32 of 47), 51% (24 of 47), and 15% (seven of 47) of patients, respectively. Partial responses (by RECIST) were reported in eight (27%) of 30 patients with measurable disease. Median time to PSA progression was 169 days (95% CI, 113 to 281 days). The median number of weeks on study was 24, and 12 (25.5%) of 47 patients remained on study > or = 48 weeks. CTCs were enumerated in 34 patients; 27 (79%) of 34 patients had at least five CTCs at baseline. Eleven (41%) of 27 patients had a decline from at least five to less than 5 CTCs, and 18 (67%) of 27 had a > or = 30% decline in CTCs after starting treatment with abiraterone acetate. Abiraterone acetate was well tolerated.

Conclusion: Abiraterone acetate has significant antitumor activity in post-docetaxel patients with CRPC. Randomized, phase III trials of abiraterone acetate are underway to define the future role of this agent.

Fig 1.

Waterfall plots of prostate-specific antigen (PSA) changes. (A) Waterfall plot of greatest percentage change in PSA of individual patients on abiraterone acetate. (B) Waterfall plot of PSA change from baseline at 12 weeks for individual patients on abiraterone acetate. Brown, gold and gray lines indicate a decline in PSA of 30%, 50% and 90%, respectively. Some patients had a PSA decline on study but this was short-lived; PSA then increased again, which explains why the week-12 and maximal PSA declines are different.

Fig 2.

Radiologic responses. (A) Patient 010 had previously experienced progression on an luteinizing hormone-releasing hormone (LHRH) agonist, flutamide, bicalutamide, docetaxel, the monoclonal antibody to IGF-1R, CP-751, 871, and the survivin inhibitor YM155. Before starting treatment with abiraterone acetate, the prostate-specific antigen (PSA) was 789, and there was evidence of nodal and bony metastatic disease. Circulating tumor cells (CTCs) were not detected. Red oval, retroperitoneal nodal disease on a baseline computed tomography (CT) scan (A). After 3 months on abiraterone acetate, PSA decreased to a nadir of 1.4 (ie, > 90% decline), and (B) the red oval shows that the nodal disease has largely disappeared. Patient 010 continues to take study drug, now in the third year of treatment. (C) Patient 025 had previously experienced progression on an LHRH agonist, antiandrogen, stilboestrol, and docetaxel. Baseline PSA was 10,325, and it decreased to a PSA nadir of 46 (ie, > 90% decline) after 4 months on abiraterone acetate. Baseline CTC count was 20, which decreased to a CTC count nadir of 0 after 4 weeks. Green oval, CT scan at baseline demonstrated an axillary nodal metastasis (C). Reduction in size is seen in a follow-up scan performed at 6 months (green oval; D). (E) Whole-body, 99mTc-MDP bone scintigraphy at baseline (again for patient 025). A response in the bony disease can be seen in (F) after 6 months on abiraterone acetate. This patient remained on study in excess of a year (ie, 482 days).

Fig 3.

Time to prostate-specific antigen (PSA) progression. Median time to PSA progression is 169 days (95% CI, 113 to 281 days).

Fig 4.

Waterfall plot of maximal circulating tumor cell (CTC) count declines in individual patients on abiraterone acetate. Twenty-six patients are featured in the plot as 1/27 patients with ≥ 5 CTCs only had a baseline measurement. Brown, gold and gray lines indicate a decline in CTC count of 30%, 50% and 90% respectively. Red dots indicate clipped CTC count values.

Fig A1.

Correlation of the maximal percentage change in prostate-specific antigen (PSA) with the maximal percentage change in circulating tumor cells (CTCs). Twenty-seven patients had five or more CTCs at baseline. This plot shows 26 patients, as one patient had only a baseline CTC measurement. Of the 10 patients with five or greater CTCs who remained on study for ≥ 24 weeks (indicated in red and gold), seven patients (70%) had an ERG gene rearrangement. However, of the 16 patients who remained on study for less than 24 weeks (indicated in blue), six of these (37.5%) had an ERG gene rearrangement.