Background: Resistance to abiraterone is hypothesized to result from increased systemic or tumor androgen production, mutations in the androgen receptor (AR) signaling pathway leading to ligand-independent, autonomous AR activity, and/or AR-independent pathways. This study investigated the clinical benefit of maximization of androgen suppression by increasing the abiraterone acetate dose at the time of initial resistance to standard-dose therapy. Methods: Eligible patients had progressive metastatic CRPC per consensus criteria. No prior abiraterone, enzalutamide, or chemotherapy was allowed. All patients started therapy with abiraterone acetate 1,000 mg daily and prednisone 5mg BID. Patients achieving any PSA decline after 3 cycles continued abiraterone until PSA or radiographic progression. At progression the abiraterone acetate dose was increased to 1,000 mg BID, prednisone was maintained at 5mg BID, and patients were monitored for response for a minimum of 12 weeks or until a second PSA or radiographic progression. Results: 41 patients were accrued from 3/2013 through 3/2014, and 13 patients currently remain on therapy. Median age was 68 (range 55-79), median ECOG PS was 0 (range 0-2), and median baseline PSA was 27.4 (range 3.9-1763). Thirteen men (31%) underwent a pre-treatment metastatic biopsy. To date 13 men who experienced progressive disease on standard-dose therapy were treated with 1,000 mg BID therapy, and are evaluable for response. No PSA declines ≥30% nor radiographic responses have been observed at the elevated-dose. Grade 3 transaminitis was observed in 1 patient on the elevated dose and resolved with dose decrease. Conclusions: Pharmacokinetic failure alone is unlikely to explain resistance to standard-dose abiraterone acetate and increasing the dose at the time of resistance may be of limited clinical utility. Analysis of serial androgen levels, abiraterone pK, and molecular and genomic analysis of circulating tumor cells and metastatic biopsies is underway, with a specific focus on the contributions of AR amplification, AR splice variation, and mesenchymal and neuroendocrine differentiation to the development of abiraterone resistance. Clinical trial information: NCT01637402