Re-treatment with radium-223: first experience from an international, open-label, phase I/II study in patients with castration-resistant prostate cancer and bone metastases

Abstract

BackgroundSix radium-223 injections at 4-week intervals is indicated for patients with castration-resistant prostate cancer and symptomatic bone metastases. However, patients usually develop disease progression after initial treatment. This prospective phase I/II study assessed re-treatment safety and efficacy of up to six additional radium-223 injections.Patients and methodsPatients had castration-resistant prostate cancer and bone metastases and six initial radium-223 injections with no on-treatment bone progression; all had subsequent radiologic or clinical progression. Concomitant agents were allowed at investigator discretion, excluding chemotherapy and initiation of new abiraterone or enzalutamide. The primary endpoint was safety; additional exploratory endpoints included time to radiographic bone progression, time to total alkaline phosphatase and prostate-specific antigen progression, radiographic progression-free survival, overall survival, time to first symptomatic skeletal event (SSE), SSE-free survival, and time to pain progression.ResultsAmong 44 patients, 29 (66%) received all six re-treatment injections. Median time from end of initial radium-223 treatment was 6 months. Forty-one (93%) reported ≥1 treatment-emergent adverse event. No grade 4–5 hematologic treatment-emergent adverse events occurred. Only one (2%) patient had radiographic bone progression; eight (18%) had radiographic soft tissue tumor progression (three lymph node and five visceral metastases). Median times to total alkaline phosphatase and prostate-specific antigen progression were not reached and 2.2 months, respectively. Median radiographic progression-free survival was 9.9 months (12.8-month maximum follow-up). Five (11%) patients died and eight (18%) experienced first SSEs. Median overall survival, time to first SSE, and SSE-free survival were not reached. Five (14%) of 36 evaluable patients (baseline worst pain score ≤7) had pain progression. After 2 years of follow-up, 28 (64%) patients died, and the median overall survival was 24.4 months.ConclusionsRe-treatment with a second course of six radium-223 injections after disease progression is well tolerated, with minimal hematologic toxicity and low radiographic bone progression rates in this small study with limited follow-up. Favorable safety and early effects on disease progression indicate that radium-223 re-treatment is feasible and warrants further evaluation in larger prospective trials.

Re‐treatment with radium‐223: 2‐year follow‐up from an international, open‐label, phase 1/2 study in patients with castration‐resistant prostate cancer and bone metastases

“…Eligibility criteria for the phase 1/2 radium‐223 re‐treatment study have been described in detail . Briefly, patients included men greater than or equal to 18 years of age with pathologically confirmed CRPC who had initially completed 6 injections of radium‐223, with no evidence of bone progression during treatment.…”

“…Assessments conducted during treatment were described in the initial report . Assessments during active follow‐up were vital signs, physical condition, complete blood counts, blood chemistries including tALP and PSA, ECOG PS, and SSE evaluations every 4 weeks for 12 weeks and then every 12 weeks until 2 years after the last dose of radium‐223 was received.…”

“…The final data cutoff was 11 June 2015, after all 44 patients had either completed treatment and the end‐of‐treatment visit (30 days after the last injection) or had discontinued treatment. Results obtained during the treatment period have been reported . The planned active follow‐up period was up to 2 years after the last dose of radium‐223; 34 patients entered follow‐up and were included in the 2‐year active follow‐up analysis.…”

“…Early results showed that re-treating patients with up to 6 additional radium-223 injections was well tolerated with favorable effects on disease progression. 8 Among 44 patients, 1 (2%) had radiographic bone progression and 8 (18%) had radiographic soft tissue progression (3 in lymph nodes and 5 in viscera). Median radiographic progression-free survival (rPFS) was 9.9 months, and median time to prostate-specific antigen (PSA) progression was 2.2 months.…”

“…An international open‐label phase 1/2 study (NCT01934790) was conducted to assess the safety of re‐treatment with up to 6 radium‐223 injections, administered at 4‐week intervals, to patients with mCRPC who previously received and tolerated a full course (6 injections) of radium‐223. Early results showed that re‐treating patients with up to 6 additional radium‐223 injections was well tolerated with favorable effects on disease progression . Among 44 patients, 1 (2%) had radiographic bone progression and 8 (18%) had radiographic soft tissue progression (3 in lymph nodes and 5 in viscera).…”