To date there is no established second line systemic therapy for patients with CRPC. HDAC inhibitors are attractive agents, particularly in prostate cancer, due to demonstrated effect in vitro on proliferation, differentiation, apoptosis, and angiogenesis coupled with anti-tumor effects in preclinical prostate cancer models.
Recognizing that tumor regressions are difficult to quantify objectively in patients with bone metastases, the clinical importance of delaying progression, and the available preclinical data on the anti-tumor effect of vorinostat, this trial was designed with a primary objective of assessing the effect of vorinostat on six month progression rates. Although, the most optimal design would have included a control arm, the progressive nature of this disease and the availability of published historical institutional data, at time of study design, on second-line chemotherapy in a similar population indicating that the expected 6-month progression rate is 84% 38
lead us to chose a single arm design. Although 41% of patients were taken off study due to toxicity thus making it difficult to assess the true efficacy of vorinostat at this dose and schedule, it is reasonable to assume that, had there been clinically meaningful anti-tumor activity, better results would have been expected. There was only one grade 4 AE, and grade 3 AE’s were predominantly constitutional in nature and not significantly different from dose limiting toxicities observed in phase I testing,21
. However, despite dose reduction in 70% of patients in this trial, 41% of patients discontinued therapy due to toxicity. Our experience is in contrast with other reports using this agent both as monotherapy and in combination with other systemic therapies in other studies. In the phase I trials, once on a tolerable dose, patients could be treated for prolonged periods of time 21, 22, 40
with chronic adverse effects of fatigue, renal insufficiency, and weight loss reversible upon discontinuation of drug.21
Dose limiting toxicities reported in phase I trials were not related to prior therapy or type of underlying malignancy and remained unpredictable within treatment cohorts.21
They were also rapidly reversible suggesting a readily reversible metabolic process.21
Safety data from 86 patients with cutaneous T-cell lymphoma treated with vorinostat leading to FDA approval of the drug, only 9.3% of patients were removed due to toxicity with 10.5% requiring dose reductions using the same dose/schedule as used in this trial; also in patients who had failed prior systemic therapies.16
Similar results were recently reported on safety data from 476 patients who participated in the vorinostat clinical trial program receiving vorinostat as single agent therapy and in combination with other systemic therapies 41
The key question is whether our observed results are a function of the patient population studied or lack of significant anti-tumor activity or both. Given the toxicity seen in this trial leading to dose reductions in 70% of patients, it is possible that suboptimal cell inhibitory plasma concentrations of vorinostat may explain why less clinical activity was seen than expected. Without pharmacokinetic (PK) data and data from other prostate cancer settings, it is difficult to conclude whether the preclinical models were poor predictors of clinical activity or whether this agent would be more efficacious in an alternative patient population or dosing schedule. One interesting observation from this population is that patients that came off study due to toxicity had significantly higher serum IL-6 levels at all time points (baseline, Day 15-Cycle 1, Day 1-Cycle, and end of study) as compared to patients removed from study for progression. It is possible that since IL-6 is associated with the inflammatory response and regulation of the systemic immune response 39
, that higher levels of serum IL-6 at baseline that were not modulated by the drug, predisposed patients to adverse side-effects leading to treatment discontinuation. IL-6 has been associated with non-responsiveness to drug therapy 29–31
. However, of the 11 patients taken off protocol due to toxicity in this study, nine patients recovered suggesting drug effect and not disease progression.
Toxicities were also prominent with no significant clinical activity in the only other reported clinical trial of HDAC inhibition in prostate cancer 42
. In this phase II trial (n=31) investigating romidepsin, a bicyclic depsipeptide that inhibits HDAC, as front line therapy for patients with metastatic CRPC, constitutional toxicities were common, with a 6 month disease control rate of 14% and PSA response rate of 7%. Observations from this and our trial raise questions regarding the impact of an androgen suppressed state as it relates to predisposing to toxicities to this class of drugs.
It is not clear why outcomes from clinical investigation of HDAC inhibitors in metastatic CRPC have not matched the promising preclinical activity and scientific rationale. However, based on the current data, further investigation of vorinostat at this dose and schedule is not recommended. Given the lack of significant clinical activity in this trial coupled with comparable outcome reported with romidepsin 42
raise concerns regarding further study of this class of drugs as single agent therapy for treatment of CRPC unless newer agents with a more favorable toxicity profile with substantial supportive preclinical data are introduced. Our observation of the association of IL-6 levels and removal from study for toxicities warrants further investigation.