Denham JW, et al. - Researchers report 10-year outcomes from the RADAR trial, wherein, men with locally advanced prostate cancer were treated with 6 months of androgen suppression and prostatic radiotherapy and were examined to determine if the addition of 12 months of adjuvant androgen suppression, 18 months of zoledronic acid, or both, could result in improved outcomes. They found that 18 months of androgen suppression plus radiotherapy vs 6 months of androgen suppression plus radiotherapy was more efficacious therapeutic option, but no benefits were reported with the addition of zoledronic acid to this treatment regimen. For men with locally advanced prostate cancer including intermediate and high risk elements, 18 months of androgen suppression with moderate radiation dose escalation vs longer durations of androgen suppression represents an effective but more tolerable option, based on the evidence from the RADAR and French Canadian Prostate Cancer Study IV trials.

Methods

• This was a randomised, phase 3, 2×2 factorial trial.
• Men who were 18 years or older with locally advanced prostate cancer (either T2b-4, N0 M0 tumours or T2a, N0 M0 tumours provided Gleason score was ≥7 and baseline prostate-specific antigen [PSA] concentration was ≥10 μg/L) were considered eligible for inclusion.
• Using computer-generated randomisation (using the minimisation technique, and stratified by centre, baseline PSA concentration, clinical tumour stage, Gleason score, and use of a brachytherapy boost), participants were randomly allocated in a 2×2 factorial design to four treatment groups, in a 1:1:1:1 ratio.
• The treatment regimen for patients in the control group was: six months of neoadjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly) and radiotherapy alone (short-term androgen suppression [STAS]); this treatment was either followed by another 12 months of adjuvant androgen suppression with leuprorelin (22·5 mg every 3 months, intramuscularly; intermediate-term androgen suppression [ITAS]), or accompanied by 18 months of zoledronic acid (4 mg every 3 months, intravenously) starting at randomisation (STAS plus zoledronic acid), or both (ITAS plus zoledronic acid).
• Starting from the end of the fifth month of androgen suppression, radiotherapy was administered to the prostate and seminal vesicles in all patients; with dosing options being 66, 70, and 74 Gy in 2-Gy fractions per day, or 46 Gy in 2-Gy fractions followed by a high-dose-rate brachytherapy boost dose of 19·5 Gy in 6·5-Gy fractions.
• Open label treatment allocation was carried out.
• Prostate cancer-specific mortality was assessed (primary endpoint) according to intention-to-treat using competing-risks methods.

Results

• This study included 1,071 men, who were enrolled and randomly assigned to STAS (n=268), ITAS (n=268), STAS plus zoledronic acid (n=268), and ITAS plus zoledronic acid (n=267) between Oct 20, 2003, and Aug 15, 2007.
• The participants were followed-up for a median duuration of 10·4 years (IQR 7·9–11·7).
• No interactions between androgen suppression and zoledronic acid were seen during follow-up and this led to collapse of treatment groups for comparing treatments according to duration of androgen suppression: 6 months of androgen suppression plus radiotherapy (6AS+RT) vs 18 months of androgen suppression plus radiotherapy (18AS+RT) and for comparing treatments according to whether or not patients received zoledronic acid.
• A total of 375 deaths were reported (200 men receiving 6AS+RT and 175 men receiving 18AS+RT), of which 143 (38%) were due to prostate cancer (81 men receiving 6AS+RT and 62 men receiving 18AS+RT).
• For 6AS+RT vs for 18AS+RT, the adjusted cumulative incidence of prostate cancer-specific mortality was 13·3% (95% CI 10·3–16·0) vs 9·7% (7·3–12·0), respectively, on analyzing by duration of androgen suppression, representing an absolute difference of 3·7% (95% CI 0·3–7·1; sub-hazard ratio [sHR] 0·70 [95% CI 0·50–0·98], adjusted p=0·035).
• No impact of zoledronic acid addition on prostate cancer-specific mortality was seen; with zoledronic acid vs without, the adjusted cumulative incidence of prostate cancer-specific mortality was 11·2% (95% CI 8·7–13·7) vs 11·7% (9·2–14·1), respectively, representing an absolute difference of −0·5% (95% CI −3·8 to 2·9; sHR 0·95 [95% CI 0·69–1·32], adjusted p=0·78).
• Although safety analysis was not prespecified for this 10-year analysis, occurrence of 1 new serious adverse event (osteonecrosis of the mandible, in a patient who received 18 months of androgen suppression plus zoledronic acid) was reported since the previous report, so finally the total number of cases of this serious adverse event was three (<1% out of 530 patients who received zoledronic acid evaluated for safety) and the total number of drug-related serious adverse events was 12 (1% out of all 1065 patients evaluable for safety).
• No deaths attributed to treatment occurred.