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.

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.