Biomodulatory Treatment of Patients with Castration-Resistant Prostate Cancer: A Phase II Study of Imatinib with Pioglitazone, Etoricoxib, Dexamethasone and Low-Dose Treosulfan

Abstract

Therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter, Phase II study, 65 patients with histologically confirmed CRPC received a biomodulatory regimen during the six-month core study. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone. The primary endpoint was prostate-specific antigen (PSA) response. Responders could enter an extension phase until disease progression or intolerable toxicity occurred. Mean PSA was 45.3 ng/mL at baseline, and 77 % of patients had a PSA doubling time <3 months. Of the 61 evaluable patients, 37 patients (60.6 %) responded or had stable disease and 23 of them (37.7 % of 61 patients) were PSA responders. Among the 23 responders mean PSA decreased from 278.9 ± 784.1 ng/mL at baseline to 8.8 ± 11.6 ng/mL at the final visit (week 24). The progression-free survival (PFS) was 467 days in the ITT population. Of the 947 adverse events, 57.6 % were suspected to be drug-related, 13.8 % led to dose adjustment or permanent discontinuation and 40.2 % required concomitant medication. This novel combination approach led to an impressive PSA response rate of 37.7 % in CRPC patients. The good PSA response and PFS rate combined with the manageable toxicity profile suggest an alternative treatment option.

Fig. 1

Study design including the main inclusion and exclusion criteria. ECOG Eastern cooperative oncology group performance status, CRPC Castration-resistant prostate cancer, PSA Prostate-specific antigen, AE Adverse event, SAE Serious adverse event

Fig. 2

Proportion of patients discontinuing study drug. 1 patient is still ongoing (at the time of manuscript submission, Oct 2014). Pts Patients, PSA Prostate-specific antigen

Fig. 3

PSA change during therapy. a Maximal PSA reduction compared to baseline for patients with PSA response, with stable disease and PSA progress. b the PSA change from baseline or LOCF. Patients with PSA response: black bars, patients with stable disease: grey bars, patients with PSA progress: white bars. PSA Prostate-specific antigen, LOCF Last observation carried forward, *Patients who entered the expansion phase of the study

Fig. 4

Resolution of bone lesions and evolution of PSA in an 80-year old patient. Bone lesions a before and b 12 months after therapy. c PSA level over time. PSA Prostate-specific antigen

Fig. 5

Quality of life: Emotional, social, physical and pain scores per visit. Emotional: squares, social: triangle, physical: circle, pain: N/N missing indicates the number of values/number of missing values

Fig. 6

Median progression-free survival (a) and overall survival (b). Circle Censored observation