Multicenter randomized phase II study comparing docetaxel plus curcumin versus docetaxel plus placebo in first-line treatment of metastatic castration-resistant prostate cancer

Abstract

Background: Metastatic castration-resistant prostate cancer (mCRPC) patients have a poor prognosis, and curcumin is known to have antineoplastic properties. On the basis of previous phase I and phase II studies, we investigated whether the association of curcumin with docetaxel could improve prognosis among mCRPC patients.

Methods: A total of 50 mCRPC patients (included from June 2014 to July 2016) treated with docetaxel in association with oral curcumin (6 g/d for 7 days every 3 weeks) versus placebo were included in this double-blind, randomized, phase II study. The primary endpoint was to evaluate the time to progression. Among the secondary endpoints, compliance, overall survival, prostate-specific antigen (PSA) response, safety, curcumin absorption, and quality of life were investigated. An interim analysis was planned in the modified intention-to-treat population with data at 6 months (22 patients per arm).

Results: Despite good compliance and a verified absorption of curcumin, no difference was shown for our primary endpoint: progression-free survival (PFS) between the placebo and curcumin groups was, respectively, 5.3 months versus 3.7 months, p = 0.75. Similarly, no difference was observed for the secondary objectives: PSA response rate (p = 0.88), overall survival (p = 0.50), and quality of life (p = 0.49 and p = 0.47).

Conclusion: Even though our previous studies and data in the literature seemed to support an association between curcumin and cancer therapies in order to improve patient outcome and prognosis, the results from this interim analysis clearly showed that adding curcumin to mCRPC patients' treatment strategies was not efficacious. The study was discontinued on the grounds of futility.

Keywords: chemotherapy; curcumin; docetaxel; metastatic castration-resistant prostate cancer; phase II; randomized trial.

FIGURE 1

Flowchart of participants: A total of 50 patients were enrolled according to the inclusion criteria. (A) 1:1 randomization were done with stratification by center, age (+/− 75 years) and mesurable lesions; 24 patients were assigned to the arm A (docetaxel + placebo) and 26 patients to the arm B (docetaxel + curcumin). The interim analysis was conducted in the modified ITT population, that is, patients who were given at least one dose of docetaxel + curcumin/placebo. Among them, six patients (two in the arm A and four in the arm B) were excluded from the analysis: Three patients were wrongly included and did not meet the inclusion criteria; three other patients died or left the study before starting the treatment

FIGURE 2

Progression‐free survival in the modified intention‐to‐treat population

FIGURE 3

Overall survival in the modified intention‐to‐treat population

FIGURE 5

Prostate‐specific antigen (PSA) evolution in the modified intention‐to‐treat (mITT) population

FIGURE 4

Waterfall plot showing the maximal percentage of change in prostate‐specific antigen (PSA) post‐therapy from baseline. The thershold of response is defined by a decrease of ≥50% during the treatment period. The last PSA value was taken for patient who discontinued the treatment before a minimum exposure of 12 weeks. (A) Waterfall plot of patients in the placebo group, n = 22. (B) Waterfall plot of patients in the curcumin group, n = 21 (one patient was excluded from the waterfall plot because no PSA value was available after baseline)

FIGURE 6

Curcumin serum concentration (p value = comparison of means to zero) (n = 6)