Randomized controlled clinical trial of a combination of somatostatin analog and dexamethasone plus zoledronate vs. zoledronate in patients with androgen ablation-refractory prostate cancer.

Background: As previously shown, the combination of standard androgen ablation therapy with somatostatin analog and dexamethasone in metastatic androgen ablation-refractory (stage D3) prostate cancer (PrCa) patients has a favorable profile of side-effects, durable objective antitumor activity (up to 60% partial response rate) and palliative effects. Bisphosphonates interfere with bone remodeling at the sites of PrCa bone metastases and have been postulated to have indirect and/or direct anti-PrCa activity.

Materials And Methods: A randomized controlled clinical trial was conducted to compare a combination of somatostatin analog (octreotide 20 mg i.m. every 28 days) and oral dexamethasone (4 mg daily for 1 month, gradually reduced to 1 mg daily by the fourth month, with a 1 mg daily maintenance dose thereafter) plus zoledronate (4 mg i.v. every 4 weeks) vs. zoledronate only. All patients in both arms remained in basic androgen blockade throughout the study.

Results: Thirty-eight stage D3 patients (mean age 72.8 +/- 6.8 years) were randomized to either treatment arm of the study. The trial was stopped after a pre-specified interim analysis met the criteria for early closure, i.e. significant difference in outcomes between the two treatment arms. Partial responses (PR, > or =50% PSA decline) were observed in 13 out of 20 patients with combination therapy vs. none with zoledronate. The combination therapy arm had significantly better outcome with respect to median progression-free survival (7.0 vs. 1.0 months, p < 0.0001), median overall survival (OS) (12.0 vs. 9.0 months, p = 0.0027), median PrCa-specific OS (defined as time from onset of therapy until PrCa-related death) (16 vs. 9.0 months, p = 0.0005) and median duration of bone pain improvement (>14 vs. 4 months p = 0.00001 by log-rank tests).

Conclusion: For androgen ablation-refractory metastatic PrCa patients under androgen ablation, the combination of dexamethasone, somatostatin analog and zoledronate offered superior objective and palliative clinical responses than zoledronate alone.