Development of bone metastases from prostate cancer: first results of the MRC PR04 randomised controlled trial (ISCRTN61384873)

Abstract

4511 BACKGROUND: The skeleton is the most common site of metastases from prostate cancer (PCa). Bisphosphonates have been shown to slow development of metastases from breast cancer and myeloma and to modify morbidity from bone metastases (BM) in PCa. METHODS: Phase III double-blind placebo-controlled randomised trial of oral bisphosphonate in men receiving standard treatment for stage T2-T4 PCa with no evidence of bone metastases and WHO performance status 0–2. The primary endpoint was time to development of symptomatic bone metastases or PCa death. Treatment consisted of either 4 tablets/day oral sodium clodronate (2,080mg Loron520) or 4 tablets/day of matching placebo control. Patients were encouraged to stay on trial medication for 5 years or until the primary trial endpoint had been reached. The trial was initiated in the pre-PSA era. RESULTS: Patients: 508 patients were randomised (target 500) over 3.5 years (June 1994 - December 1997): 254 to active (A), 254 to control (C). Baseline characteristics were well balanced with stage T2 - 53%, T3 - 42% and T4 - 4%; WHO performance status 0 - 79%; median age 69 years, overall. The median follow-up time is 7 years for patients last alive. Medication & Toxicity: All patients have completed their allocated trial medication. The main reasons for stopping trial drug were: 5 years of trial drug (Active 38%, Control 46%), gastro-intestinal (GI) problems (Active 15%, Control 8%) and symptomatic bone progression (Active 9%, Control 9%). The proportion of patients still on trial medication at 3 years was 54% for Active and 69% for Control. 383 adverse events were reported, 202 in the Active group, 181 in Control. The most common reported AEs were GI problems (43% Active, 38% Control) and raised LDH (15% Active, 3% Control). Symptomatic bone metastases or prostate cancer deaths: With 131 events there was no evidence of a difference; a trend to better outcome for Control was observed: HR=1.29 (95%CI 0.92,1.82; p=0.13). Overall survival: there was no evidence of a difference with 170 deaths reported: HR=1.03 (95%CI 0.76,1.39; p=0.86). Combining the arms, overall survival at 5-yrs was 78%. COMMENTS: These initial results suggest, at best, no improvement in terms of the primary outcome of symptomatic bone metastases or prostate cancer death for patients with locally advanced prostate cancer with the use oral sodium clodronate. This outcome is qualitatively different to the published results of the sister trial, MRC PR05, in hormone-sensitive metastatic disease and to studies with zoledronic acid in patients with hormone-refractory metastatic disease. The outcomes for all patients were much better than anticipated in the design of this trial, therefore the observed event rate was lower than expected. Further adjuvant studies with newer bisphosphonates are urgently required before their routine adoption as adjuvant treatment in PCa. Benefits from bisphosphonates in advanced disease cannot be assumed to apply in the adjuvant setting nor can a class effect across different tumour types be assumed. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche (Brussels, as UK PI on other Ph II study) Roche (Brussels, as UK PI on other Ph II study)