Results of the phase III ASCENT2 trial found that the combination of docetaxel and high-dose calcitriol provided no survival benefit compared with docetaxel and prednisone in men with progressive castration-resistant prostate cancer (CRPC). These findings, recently reported at the 2010 ASCO Annual Meeting by Howard I. Scher, MD, of Memorial Sloan-Kettering Cancer Center, fail to support data from a previous phase II trial that had suggested a survival benefit with the docetaxel/calcitriol regimen.¹

ASCENT

Calcitriol, a naturally occurring hormone and the principal active metabolite of vitamin D, has been shown to inhibit the growth of prostate cancer cells and to exert additive or synergistic effects when combined with chemotherapy, including docetaxel. A previous phase II study of high-dose calcitriol plus weekly docetaxel showed promising activity in progressive CRPC. The randomized phase II trial, known as ASCENT (AIPC [Androgen-Independent Prostate Carcinoma] Study of Calcitriol Enhancing Taxotere), evaluated whether the addition of DN-101, an oral high-concentration formula of calcitriol, to weekly docetaxel could increase the prostate-specific antigen (PSA) response rate in men with metastatic CRPC.²

In this trial, 250 patients were randomized to treatment with docetaxel at 36 mg/m2 IV for 3 of 4 weeks plus either high-dose calcitriol (45 µg of DN-101) or placebo. PSA responses were noted in 63% of patients in the ASCENT arm and 52% in the control arm (P = .07). Although this trial failed to meet the primary endpoint of a predefined improvement in the probability of at least a 50% reduction in PSA from baseline, longer follow-up suggested that survival was greater for patients on the ASCENT regimen compared with placebo (median = 24.5 vs 16.4 months). Interestingly, a possible reduction in the incidence of gastrointestinal (GI) and thromboembolic events was also noted on the ASCENT arm.

ASCENT2

A subsequent phase III trial, ASCENT2, evaluated whether the addition of DN-101 to weekly docetaxel prolongs survival and reduces toxicity compared with docetaxel given every 3 weeks. Men were eligible for this trial if they had metastatic CRPC with disease progression, Eastern Cooperative Oncology Group performance status of 0 to 2, serum testosterone level less than 50 ng/mL, and normal renal and hepatic function. No prior chemotherapy was allowed. Patients (N = 953) were randomly assigned in a 1:1 ratio to the ASCENT regimen (36 mg/m2 of docetaxel, 45 µg of DN-101, and 24 mg of dexamethasone weekly for 3 of every 4 weeks) or the control arm (5 mg of prednisone twice daily, 75 mg/m2 of docetaxel, and 24 mg of dexamethasone every 3 weeks). The primary study endpoint was overall survival, with secondary endpoints of thromboembolic event rate, duration of skeletal-related event-free survival, and safety.

The planned enrollment was 900 patients, which was amended to 1,200 patients in April 2007 to increase the power of the trial. However, 6 months later the trial was halted by the data safety monitoring board due to an increased number of deaths on the ASCENT arm compared with the control arm (17.0% vs 10.2%). With a median follow-up of 11.7 months, median overall survival was 16.8 months (95% CI = 15.8-19.3) for men on the ASCENT arm and 19.9 months (95% CI = 18.6-22.7) for those on placebo (P = .002). Multivariate analysis confirmed that treatment with the ASCENT regimen was associated with a statistically shorter survival compared with control (HR = 1.33, P = .019). A competing risk analysis confirmed that treatment assignment (or treatment with ASCENT) was associated with prostate cancer-specific mortality but not with death from other causes after adjusting for important prognostic factors.

Patient baseline demographics were well balanced between treatment arms. The toxicity profiles were also similar for both groups, noted Dr. Scher, including rates of severe adverse events. However, dose modification due to docetaxel toxicity was more common with ASCENT than with control treatment (229 vs 160 patients). The possible protective effect of this regimen on GI and thromboembolic events previously seen in the first ASCENT study was not confirmed in the present trial.

Docetaxel Schedules

The similarity in survival times in trials of weekly docetaxel suggests that the addition of DN-101 did not adversely affect outcomes. In the TAX 327 trial, use of weekly docetaxel resulted in slightly shorter survival relative to docetaxel every 3 weeks used in the control arm, although the study was not designed to compare the two arms.³ The inferior survival observed in ASCENT2 may have been related to the weekly docetaxel used on the ASCENT arm compared with the every-3-week dosing on the control arm.

Ian Tannock, MD, PhD, DSc, of the Princess Margaret Hospital and University of Toronto, noted that although the trial may be criticized for using different schedules of docetaxel, "this was a pragmatic design, based on preclinical data and a prior phase II study that allowed maximum interaction of the two drugs." The results underscore the importance of confirming apparently promising phase II results, concluded Dr. Scher. ■

References

1. Scher HI, Chi KN, De Wit R, et al: Docetaxel (D) plus high-dose calcitriol versus D plus prednisone (P) for patients (Pts) with progressive castration-resistant prostate cancer (CRPC): Results from the phase III ASCENT2 trial. Abstract 4509.  Presented June 6, 2010.

2. Beer TM, Ryan CW, Venner PM, et al: ASCENT Investigators. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: A report from the ASCENT Investigators. J Clin Oncol 25:669-674, 2007.

3. Tannock IF, de Wit R, Berry WR, et al; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004.