An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223

Abstract

Background: Baseline clinical variables are prognostic for overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). Their prognostic and predictive value with agents targeting bone metastases, such as radium-223, is not established.

Patients and methods: The radium-223 ALSYMPCA trial enrolled patients with CRPC and symptomatic bone metastases. Prognostic potential of baseline variables was assessed using Cox models. Percentage changes in biomarker levels from baseline were evaluated during the trial period; changes from baseline to week 12 were evaluated for association with OS and surrogacy.

Results: Eastern Cooperative Oncology Group performance status, total alkaline phosphatase (tALP), lactate dehydrogenase (LDH), and prostate-specific antigen (PSA) at baseline were associated with OS (P ≤ 0.0003) in the intent-to-treat population (radium-223, N = 614; placebo, N = 307). tALP declined from baseline within 4 weeks after beginning radium-223, by week 12 declining in 87% of radium-223 and 23% of placebo patients (P < 0.001). LDH declined in 51% and 34% (P = 0.003), whereas PSA declined in 27% and 14% (P = 0.160). Mean tALP change from baseline was 32.2% decrease with radium-223 and 37.2% increase with placebo. Radium-223 patients with tALP decline from baseline to week 12 (confirmed ≥3 weeks from week 12) had 55% lower risk of death (hazard ratio = 0.45; 95% CI 0.34-0.61) versus those with no confirmed tALP decline. Proportional treatment effect (PTE) values for tALP, LDH, and PSA changes from baseline at week 12 as OS surrogate markers were 0.34 (95% CI: 0-0.746), 0.07 (95% CI: 0-0.211), and 0 (95% CI: 0-0.082), respectively.

Conclusions: Significant tALP declines (versus placebo) occurred as early as 4 weeks after beginning radium-223 therapy. tALP or LDH declines at 12 weeks correlated with longer OS, but did not meet statistical surrogacy requirements. Dynamic changes in tALP and LDH during radium-223 treatments may be useful to monitor, but do not serve as surrogates for survival.

Keywords: ALSYMPCA; CRPC; alkaline phosphatase; lactate dehydrogenase; prostate-specific antigen; radium-223.

Figure 1.

tALP and LDH dynamics in the ITT population. Mean percentage change in (A) baseline tALP and (B) baseline LDH at the end of each treatment cycle (6 cycles) and two follow-up visits. Six patients in the radium-223 arm and 1 in the placebo arm did not have baseline LDH determinations and were excluded from this analysis. ITT, intent to treat; LDH, lactate dehydrogenase; tALP, total alkaline phosphatase.

Figure 2.

Overall survival in the radium-223 cohort with and without a confirmed decline in (A) baseline tALP and (B) baseline LDH at week 12. Confirmed decline was defined as any decrease from baseline at week 12, confirmed ≥3 weeks later. LDH, lactate dehydrogenase; tALP, total alkaline phosphatase.

Figure 3.

Relationship between percentage change in (A) tALP, (B) LDH, and (C) PSA levels from baseline and risk of death relative to no change in tALP, LDH, or PSA in the ITT population with baseline marker analyses. The red lines in (A) define the area of decreasing risk of death with decreases in tALP from their baseline level. To make (C) PSA comparable to (A) tALP, its x axis was truncated to include only patients with PSA percentage changes from baseline between -100% and 300%; 46 of 910 (5.1%) patients with percentage changes in PSA >300% were excluded. LDH, lactate dehydrogenase; PSA, prostate-specific antigen; tALP, total alkaline phosphatase.