Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer.
OBJECTIVE
Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy.


METHODS
Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was > or = 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated.


RESULTS
A > or = 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from > or = 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen.


CONCLUSIONS
AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.
Danila
Daniel C
DC
Department of Medicine, Joan and Sanford E. Weill College of Medicine of Cornell University, Ithaca, NY, USA. Scherh@mskcc.org
Morris
Michael J
MJ
de Bono
Johann S
JS
Ryan
Charles J
CJ
Denmeade
Samuel R
SR
Smith
Matthew R
MR
Taplin
Mary-Ellen
ME
Bubley
Glenn J
GJ
Kheoh
Thian
T
Haqq
Christopher
C
Molina
Arturo
A
Anand
Aseem
A
Koscuiszka
Michael
M
Larson
Steve M
SM
Schwartz
Lawrence H
LH
Fleisher
Martin
M
Scher
Howard I
HI
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes; D000737:Androstenols / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018450:Disease Progression; D000077143:Docetaxel; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D006929:Hyperaldosteronism / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D009919:Orchiectomy; D011241:Prednisone / Q000008:administration & dosage; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D043823:Taxoids / Q000627:therapeutic use; D016896:Treatment Outcome
D000736:Androstenes; D000737:Androstenols; D005938:Glucocorticoids; D043823:Taxoids; D000077143:Docetaxel; D017430:Prostate-Specific Antigen; C089740:abiraterone; D011241:Prednisone