Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer

Abstract

Purpose: Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and anti-metastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial.

Experimental design: Two hundred and one (134 tasquinimod and 67 placebo) men with mCRPC were evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS).

Results: With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-to-symptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit.

Conclusions: The survival observed in this trial of men with minimally symptomatic mCRPC suggests that the prolongation in PFS with tasquinimod may lead to a survival advantage in this setting, particularly among men with skeletal metastases, and has a favorable risk:benefit ratio.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

Ö. Nordle and G. Forsberg are employees and shareholders of Active Biotech. A.J. Armstrong has received commercial research funding from Active Biotech and is consultant/advisory board member for Ipsen. A.J. Armstrong has received commercial research funding from Active Biotech, Dendreon, Medivation, Janssen, and Sanofi Aventis; A.J. Armstrong holds a consultant/advisory board position with Active Biotech, Dendreon, Medivation, Janssen, and Bayer. M. Häggman is a consultant for Active Biotech. W.M. Stadler has received commercial research funding from Active Biotech. V. Assikis has received honoraria from the Speakers Bureau of Astellas, Janssen, and Dendreon and is a consultant/advisory board member for Astellas, Dendreon, and Janssen. JE Damber receives research funding from Active Biotech and is a consultant to Ipsen. M.A. Carducci is a consultant/advisory board member for Active Biotech. R. Pili receives research funding from Active Biotech. No potential conflicts of interest were disclosed by the other authors.

©2013 AACR.

Figures

Figure 1

OS and time to symptomatic progression. A, overall survival in the ITT population with median OS 33.4 versus 30.4 months (P = 0.49; HR, 0.87; 95% CI, 0.59–1.29; n = 201; tasquinimod/placebo n = 134/67; events = 71/40). B, OS in the bone-metastatic disease subgroup identified by PCWG2 with median OS 34.2 versus 27.1 months (P = 0.19; HR, 0.73; 95% CI, 0.46–1.17; n = 136; tasquinimod/placebo n = 92/44; events = 47/28). C, OS in subgroups based on open-label treatment, that is, tasquinimod entering open-label/placebo cross-over/tasquinimod not entering open-label/placebo non–cross-over n = 34/41/100/26. Events = 11/20/60/20; median OS = not reached/39.6/23.4/17.8 months, n = 201. D, time to symptomatic progression in the ITT population. Number of events tasquinimod/placebo n = 9/14; HR, 0.42; 95% CI, 0.18–0.98; P = 0.039.

Figure 2

HRs for the risk of death in subgroups based in the intent-to-treat population (A) and the PCWG2-defined subgroup of men with bone-metastatic disease (B). The dashes indicate that median survival has not been reached in that subgroup. Horizontal bars, 95% CIs.

Figure 3

Normalized box-plot analyses of the biomarkers bone alkaline phosphatase (BAP), C-reactive protein (CRP), LDH, TGFβ-1, TSP-1, VEGF-A, VEGF-C, and sRAGE over time of the double-blind part of the study (baseline, week 4, and week 8). The median baseline values for the biomarkers were (tasquinimod/placebo): BAP (20.9/21.3 μg/L), CRP (3.0/2.4 mg/dL), LDH (202/206 U/L), TGF-β1 (5940/4820 ng/L), TSP-1 (1410/1330 μg/L), VEGF-A (45.3/40.2 μg/L), VEGF-C (740/799 ng/L), and sRAGE (1280/1060 ng/L). Red refers to tasquinimod treatment whereas blue refers to placebo.

Figure 4

A, number and grade of gastrointestinal adverse events over treatment time. B, forest plot showing HRs for various adverse events in patients younger or older than 75 years. A-A indicates the tasquinimod treatment group whereas P-A indicates the placebo treatment group. A-A OL indicates tasquinimod-treated men who continued on tasquinimod open-label after 6 months, whereas P-A OL indicated the placebo-treated men who crossed over to tasquinimod at 6 months or progression.