Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in Patients With Docetaxel-Treated Castration-Resistant Prostate Cancer

Abstract

A B S T R A C T PurposePersistence of ligand-mediated androgen receptor signaling has been documented in castrationresistant 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. Patients and MethodsFifty-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 Ն 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. ResultsA Ն 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 Ն 5 to Ͻ 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. ConclusionAA 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.

Phase II trial of cisplatin plus prednisone in docetaxel-refractory castration-resistant prostate cancer patients

“…The major limitations of our study are the limited sample size, the lack of a control arm and the use of the PCWG1, instead of the PCWG2 criteria, as it has occurred for other recently published trials [10,11].…”

“…In fact, as suggested by the PCWG1 criteria [9], PSA response rate has been used as primary end point and employed to calculate the sample numerosity in several recently published trials [10,11].…”

AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

“…The change in terminology reflects emerging data that show prostate cancer in this resistant state to have a continued dependency upon AR signaling. This is exemplified by the recent overall survival benefit shown in patients with CRPC following treatment with either abiraterone acetate or enzalutamide (17)(18)(19)(20)(21)(22). Abiraterone acetate inhibits 17-a-hydroxylase/17,20-lyase (CYP17) activity resulting in a reduction in residual androgens synthesized by the adrenals and potentially the prostate tumor itself (23).…”

Revisiting the Role of Antiandrogen Strategies in Ovarian Cancer

“…Newer promising treatments that are more potent suppressors of the AR axis or that inhibit androgen and estrogen synthesis should be evaluated in clinical trials for EOC. For example, abiraterone has been proven to be beneficial in prostate cancer patients who have progressed on previous treatment with GnRH analogs [81].…”