Abstract A221: A phase II study of SB939 in patients with recurrent or metastatic castration resistant prostate cancer (CRPC).

Abstract

Abstract Background: SB939 is a potent oral inhibitor of class I, II and IV histone deacetylases (HDACs) with high tumor tissue selectivity. These 3 classes of HDAC are highly expressed in prostate cancer and associated with poor clinical outcomes. HDAC inhibition has been shown to abrogate androgen receptor signaling via inactivation of HSP90, and may have relevance particularly in TMPRSS2-ERG fusion positive prostate cancer. Methods: In this multicenter phase II study, pts with CRPC received SB939 60mg every other day 3 times per week × 3 weeks on a 28-day cycle. Primary endpoints were PSA response rate (RR) (>50% decline from baseline for > 4 weeks) and progression free survival (PFS). Secondary endpoints included objective response rate; response duration, overall survival; circulating tumor cell (CTC) enumeration at baseline, 6 and 12 weeks; TMPRSS2-ERG fusion analysis; correlative analysis of archival tissue; and safety. Planned sample size was 29 pts, the hypotheses (PSA RR <2% vs. ≥15%) could be tested at 10% and levels. Results: Twenty-nine pts have been accrued. Median age is 69, 25 pts had received no prior chemotherapy, ECOG performance status was 0/1 in 48%/52% of pts. Bone/lymph node/visceral metastases were present in 86%/69%/10% of pts. The median number of cycles of SB939 administered is 2 (range 1–6) with 7 pts still continuing treatment. Adverse events were generally grade 1–2, with 5 patients experiencing grade 3 events (fatigue (5 pts), vomiting (1 pt) and dyspnea (1pt)). To date, a confirmed PSA response has been noted in 2 pts (7%). In 8 RECIST-evaluable pts, there were no objective responses, and 3 pts had stable disease lasting from 3.4 to 5.6 months. CTC favorable conversion (from ≥5 at baseline to <5 at 6 or 12 weeks) was observed in 9/14 evaluable patients (64%) and unfavorable CTC levels (>5) at 6 weeks correlated with PSA progression. RT-PCR for presence of TMPRSS2-ERG transcripts from whole blood and FISH analyzes of CTC and archival tissue for TMPRSS2-ERG fusion and PTEN deletion status are ongoing. Conclusion: SB939 is well tolerated and has shown early evidence of activity in CRPC. Analysis of more mature data will be required to determine whether this agent warrants further study, and whether TMPRSS2-ERG status might predict for response to SB939. Supported by grants from the Canadian Cancer Society and the Ontario Institute for Cancer Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A221.