Romidepsin (FK228), a histone deacetylase inhibitor: Final results of a phase II study in metastatic hormone refractory prostate cancer (HRPC)

Abstract

15507 Background: Romidepsin is a bicyclic depsipeptide that inhibits histone deacetylase (HDAC). Translocations fusing TMPRSS2 gene and ERG oncogenic factor is associated with elevated HDAC-1 expression. HDAC inhibition results in accumulation of hyperacetylated histone proteins resulting in G1 and G2/M arrest, differentiation of transformed cells and apoptosis. Romidepsin can also inhibit HSP90, ablating androgen receptor expression. This is the 1st study to report activity of an HDAC inhibitor in HRPC. Methods: Romidepsin was administered intravenously at 13mg/m2 on days 1, 8 and 15 of a 28-day schedule. A 2-stage design was used. Eligibility criteria included: no prior chemotherapy, metastatic disease, QTcB <470msec, Karnofsky PS =80. The primary endpoint was to determine rate of disease control (complete response [CR], partial response [PR], stable disease [SD] for 6 months). Secondary endpoints were PSA response rate (RR), time to PSA and objective disease progression, safety profile, effect on disease related symptoms and pharmacokinetics (PK) of romidepsin. Results: Thirty-one patients were enrolled. Median age: 64 years (range 43–82). Twenty-one patients are evaluable for radiological and PSA response: 1 patient achieved a confirmed radiological PR lasting >6 months (m), and 2 confirmed SD for 6m. Four patients had SD lasting 5m (n=2) and 4m (n=2). The PSA RR was 7%. A 3rd patient had a 40% fall in PSA lasting 5m. The most common drug related adverse events were (all grades, %): nausea (84%), fatigue (77%), vomiting (65%), anorexia (61%), constipation (45%), dysguesia (35%), diarrhea (32%), thrombocytopaenia (32%), anemia (28%) and neutropenia (25%). There were no grade 4 events. Non-specific asymptomatic ST segment changes on ECG were seen in 15 % of patients; there was no evidence of significant QTc prolongation on ECG confirmed by manual calculation. Conclusions: Treatment with single agent romidepsin is associated with a disease control rate of 14% and a PSA RR of 7%. Constitutional toxicities are prominent, no grade 4 events have been observed and only minimal cardiac toxicity has been reported. Further investigation in combination with other active agents in HRPC is warranted. [Table: see text]