Fifty-four CRPC patients were recruited to this phase I/II trial between December 13, 2005 and November 28, 2007,15
and six patients continue on single-agent abiraterone acetate. Forty-two patients were treated at 1,000 mg (including nine patients in the phase I portion of the study treated at 1,000 mg); the other 12 patients were treated at 250, 500, 750, and 2,000 mg (three patients at each dose level). As defined a priori in this phase I/II trial protocol, all patients treated at 1,000 mg were included in this phase II antitumor activity analysis. lists the demographics and clinical characteristics of the 42 patients treated at 1,000 mg. The median number of lines of prior hormonal treatments was three. All patients had experienced progression on LHRH analogs, and 41 of 42 patients had experienced progression on antiandrogens; one patient had experienced progression on LHRH analogs and diethylstilboestrol but had not received an antiandrogen. Fourteen (33%) of 42 patients had experienced progression on dexamethasone, and 20 (48%) of 42 patients had experienced progression on diethylstilboestrol, including seven (17%) of 42 patients on both. Two patients had experienced progression on ketoconazole. Twenty-four patients (57%) had measurable disease on CT scan at baseline, and 32 (76%) of 42 patients had bone metastasis on bone scan; 17 (40%) of 42 patients had ≥ 5 CTCs/7.5 mL at baseline.
Baseline Patient Demographics and Clinical Characteristics of Patients Treated With Abiraterone Acetate 1,000 mg
PSA, CTC Count, and Radiologic Evidence for Antitumor Activity
A decline in PSA of ≥ 50% was observed in 28 (67%) of 42 patients, and 30 (71%) of 42 and eight (19%) of 42 patients had a decline in PSA of ≥ 30% and ≥ 90%, respectively. The change in PSA from baseline at 12 weeks and the maximal change at any time point after 12 weeks are presented in . One of the two patients who had previously experienced progression on ketoconazole and hydrocortisone had a decline in PSA from 79 to 10.9 ng/mL, which is ongoing after 230 days of treatment. By RECIST criteria, 24 patients had measurable disease on CT scan, with nine patients (37.5%) having tumor regression that constituted a partial response (); overall, 16 patients (66%) had no evidence of progression at 6 months. Furthermore, 10 (59%) of 17 patients had a decline in CTC count from ≥ 5to less than 5/7.5 mL, and 12 (70%) of 17 patients had a decline of ≥ 30% after starting treatment with abiraterone acetate.
Fig 1 Changes in prostate-specific antigen (PSA) with abiraterone acetate. Waterfall plot showing maximal percentage change in PSA from baseline with single-agent abiraterone acetate 1,000 mg at (A) 12 weeks and (B) any time point after 12 weeks. The dashed (more ...)
Fig 2 Radiologic responses to abiraterone acetate. (A) Patient 203 had previously experienced progression on luteinizing hormone–releasing hormone (LHRH) agonists, bicalutamide, diethylstilboestrol, and the histone deacetylase inhibitor FK228. Before (more ...)
A syndrome of secondary mineralocorticoid excess characterized by hypokalemia (37 of 42 patients; 88%), hypertension (17 of 42 patients; 40%), and fluid overload (13 of 42 patients; 31%) was reported. This was managed by eplerenone 50 to 200 mg daily except in three patients who required glucocorticoid replacement for symptomatic fluid overload; in two patients, this was associated with migrainous headaches. Magnetic resonance imaging of the brain was normal in both patients. Another patient with a prior history of asthma required high-dose corticosteroids for worsening asthma and was subsequently maintained on dexamethasone 0.5 mg daily. Hot flushes developed in four of 42 patients; venlafaxine was required to control symptoms in two patients. Two patients (5%) developed asymptomatic grade 3 transaminase elevation 10 weeks and 27 weeks after starting abiraterone acetate. Interruption of treatment resulted in complete resolution. One patient was rechallenged with abiraterone acetate 750 mg, and the transaminase elevation recurred, suggesting that this event was secondary to study treatment. Another patient suffered grade 2 asymptomatic transaminase elevation 16 weeks after starting abiraterone acetate 1,000 mg, but this resolved after temporary discontinuation of treatment, and a dose of 750 mg was then administered uneventfully. Four patients developed grade 1 headaches, and five patients complained of grade 1 joint aches; these symptoms occurred intermittently on abiraterone acetate and did not necessitate treatment interruption. No other adverse events considered related to abiraterone acetate of grade ≥ 2 severity or occurring in two or more patients were reported.
The median follow-up time for the 42 patients treated at 1,000 mg was 505 days (95% CI, 457 to 552 days), with a median TTPP on abiraterone acetate alone of 225 days (95% CI, 162 to 287 days; ). The median TTPP for the patients treated at 1,000 mg who had a ≥ 50% decline in PSA was 253 days (95% CI, 122 to 383 days), and the median TTPP for the patients who had a ≥ 90% decline in PSA was 393 days (95% CI, 252 to 533 days). Fourteen patients were censored for this analysis; five patients continued on single-agent abiraterone acetate at the date of data cutoff, and nine patients started dexamethasone or stopped abiraterone acetate without confirmed PSA progression after 12 weeks (Appendix Table A1). The median follow-up time for all 54 phase I/II patients who received any amount of study medication was 588 days (95% CI, 409 to 767 days), with a median TTPP on abiraterone acetate alone of 229 days (95% CI, 157 to 301 days) and median TTPP for patients who had a ≥ 50% and ≥ 90% decline in PSA of 339 days (95% CI, 136 to 542 days) and 477 days (95% CI, 350 to 604 days), respectively. Sixteen patients were censored for this analysis; six patients continued on single-agent abiraterone acetate at the date of data cutoff, and 10 patients started dexamethasone or stopped abiraterone acetate without confirmed PSA progression after 12 weeks (Appendix Table A1).
Fig 3 Time on treatment with abiraterone acetate. (A) Kaplan-Meier (KM) plot showing time to prostate-specific antigen progression (TTPP) on abiraterone acetate alone for 42 patients treated at 1,000 mg. (B) KM plot for TTPP for all patients (N = 54) after (more ...)
Addition of Corticosteroids at Progression on Abiraterone Acetate Alone
To date, 39 of 54 patients in this phase I/II study have received abiraterone acetate in combination with dexamethasone 0.5 mg daily; 14 continued on this combination at date of data cutoff (Appendix Table A1). The median TTPP from addition of dexamethasone until stopping both abiraterone acetate and dexamethasone (n = 39) was 151 days (95% CI, 117 to 185 days). Thirty patients received the combination for ≥ 12 weeks after progression on abiraterone acetate alone and were thus assessable for magnitude of PSA decline; 24 patients experienced progression on the combination (Appendix Table A1). Eleven of these 30 patients had previously experienced progression on dexamethasone (group I), and 19 of 30 were dexamethasone naive (group II); four (36%) of 11 patients in group I and six (32%) of 19 patients in group II had ≥ 50% declines in PSA (Appendix Fig A1, online only). The median TTPP for all 54 patients from start of abiraterone acetate until PSA progression on the combination (n = 25) or on abiraterone acetate alone if dexamethasone was not used (n = 3) was 420 days (95% CI, 259 to 580 days; ); the median TTPP was 372 days (95% CI, 55 to 688 days) for patients who previously experienced progression on dexamethasone (group I) and 361 days (95% CI, 241 to 480 days) for dexamethasone-naive patients (group II). The remaining 26 patients were censored at the date of data cutoff either because they continued on treatment (n = 20) or they had stopped treatment without confirmed criteria for PSA progression (n = 6; Appendix Table A1).
Predictors of Response to Abiraterone Acetate
All 54 patients who received any amount of single-agent abiraterone acetate were included in this analysis. Pretreatment levels of DHEA, DHEA-S, androstenedione (continuous variable), and estradiol were associated with increased probability of a ≥ 50% PSA decline on abiraterone acetate and with median TTPP calculated from start of abiraterone acetate until PSA progression on dexamethasone and abiraterone acetate (or on abiraterone acetate alone if dexamethasone was not added; Tables and ).
Association of Pretreatment Serum Investigations (continuous variable) in Patients Who Received Any Amount of Abiraterone Acetate (N = 54) With Probability of a ≥ 50% PSA Decline
Association of Pretreatment Serum Investigations (continuous variable) in Patients Who Received Any Amount of Abiraterone Acetate (N = 54) With TTPP on Abiraterone Acetate and Dexamethasone