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

Abstract

BackgroundBaseline 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 methodsThe 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.ResultsEastern 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.ConclusionsSignificant 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.

The Contemporary Use of Radium-223 in Metastatic Castration-resistant Prostate Cancer

“…6 Exploratory analyses from the phase III study investigated the effect of radium-223 on changes in tALP, PSA, and LDH levels. 40 Radium-223 treatment led to a rapid and sustained decrease in tALP levels from baseline through treatment and follow-up compared with placebo (where tALP levels increased during the study). At week 12 (after 3 radium-223 cycles), 87% of patients had a tALP decrease from baseline compared with 23% of patients receiving placebo (P < .001).…”

“…Furthermore, patients receiving radium-223 who experienced a confirmed tALP decline at week 12 had a longer overall survival than those who did not (HR, 0.45; 95% CI, 0.34-0.61). 40 In contrast, radium-223 had a relatively modest effect on PSA kinetics, with 27% of patients showing a PSA decline at week 12 compared with 14% in the placebo group (P ¼ .160). 40 Similar findings on ALP were reported in the radium-223 iEAP.…”

“…Baseline factors including those related to levels of lactate dehydrogenase (LDH), prostate-specific antigen (PSA), alkaline phosphatase (ALP), hemoglobin, pain, and Eastern Cooperative Oncology Group performance status may be useful in stratifying patients with better prognosis and therefore, those who are earlier in their disease course. 31,37,38,40 In post hoc analyses, patients with good prognostic factors have been shown to be more likely to complete 6 cycles of radium-223 and, consequently, derive the most benefit from receiving radium-223. 37,38 In relation to symptoms, the definition of 'symptomatic' used in the ALSYMPCA study (regular use of analgesic medication [paracetamol to opioid analgesics] or treatment with external beam radiation therapy required for cancer-related bone pain within the previous 12 weeks) 6 is considered by many clinicians to have been too broad.…”

Ra-223 dichloride management in a Nuclear Medicine Unit: experience of a referral institution

“…A separated analysis of CRPC patients treated with Ra-223 in phase II studies demonstrated that a decline in serum t-ALP during treatment was associated with a signi icantly better Overall Survival [35], suggesting that total ALP may be a useful dynamic marker to monitor as an indication of disease status. Further exploratory analysis of ALSYMPCA data on t-ALP dynamics during Ra-223 treatment con irmed that t-ALP decline at 12 weeks correlated with longer OS, but this biomarker did not meet statistical requirements as surrogate marker for survival [36].…”

Symptom assessment to guide treatment selection and determine progression in metastatic castration-resistant prostate cancer: Expert opinion and review of the evidence

“…For patients on radium-223, progression is determined largely by symptoms, and biomarkers such as alkaline phosphatase and lactate dehydrogenase may be more useful to monitor than PSA, as PSA response does not accurately predict extent of skeletal metastases or treatment effects on disease progression in bone. 28 It should be noted that in Canada the timing and sequence of treatment decisions are also shaped by different reimbursement policies in each province such that access to some agents or specific sequences may be limited.…”