No Mortality Differences With Intermediate- or Short-Term Androgen Suppression With or Without Zoledronic Acid in Locally Advanced Prostate Cancer
In a phase III Australian/New Zealand trial (TROG 03.04 RADAR) reported in The Lancet Oncology, Denham et al found no differences in prostate cancer–specific or all-cause mortality with intermediate-term androgen suppression and radiotherapy or short-term suppression plus radiotherapy with or without zoledronic acid in patients with locally advanced prostate cancer. Intermediate-term androgen suppression plus zoledronic acid vs short-term androgen suppression was associated with reduced risk for prostate-specific antigen (PSA) progression, and short-term androgen suppression plus zoledronic acid vs short-term androgen suppression was associated with increased risk of bone progression.
Study Details
In this open-label 2×2 factorial trial, 1,071 men with locally advanced disease were randomly assigned between October 2003 and August 2007 to receive 18 months of androgen suppression (leuprorelin at 22.5 mg intramuscularly every 3 months) given as neoadjuvant therapy for the first 6 months plus radiotherapy (intermediate-term) with (n = 267) or without (n = 268) 18 months of zoledronic acid (4 mg intravenously every 3 months) or 6 months of neoadjuvant androgen suppression plus radiotherapy (short-term) with (n = 268) or without (n = 268) zoledronic acid. Patients had to have T2a,N0,M0 prostatic adenocarcinoma with prostate-specific antigen (PSA) ≥ 10 μg/L and a Gleason score ≥ 7 or T2b–4,N0,M0 tumors regardless of PSA and Gleason score.
The initial primary endpoint was PSA relapse-free survival. The primary endpoint was changed in December 2011 to prostate cancer–specific mortality after other data indicated that PSA progression was not strongly prognostic for metastases or death in this setting. The current analysis is the first preplanned assessment of endpoints, at 5 years after treatment. Analysis was performed in the intention-to-treat population.
No Mortality Differences
Median follow-up was 7.4 years. There were no significant differences in prostate cancer–specific mortality among groups (P = .38), with cumulative rates being 4.1% in the short-term androgen suppression group, 7.8% in the short-term androgen suppression plus zoledronic acid group, 7.4% in the intermediate-term androgen suppression group, and 4.3% in the intermediate-term androgen suppression plus zoledronic acid group. There were no significant differences among groups in all-cause mortality (P = .84), with cumulative rates being 17.0%, 18.9%, 19.4%, and 13.9%.
Secondary Endpoints
With regard to other secondary endpoints, there were no significant differences among the short-term androgen suppression, short-term androgen suppression plus zoledronic acid, intermediate-term androgen suppression, or intermediate-term androgen suppression plus zoledronic acid groups with regard to local progression (4.1%, 6.1%, 1.5%, and 3.4%; P = .12) or distant progression (14.7%, 17.3%, 14.2%, and 11.1%; P = .38).
Significant differences were observed in bone progression (7.5%, 14.6%, 8.4%, and 7.6%; P = .016), with risk increased with short-term androgen suppression plus zoledronic acid vs short-term androgen suppression (sub-hazard ratio [SHR] = 1.90, P = .012), and in PSA progression (34.2%, 39.6%, 29.2%, and 26.0%, P = .0006), with risk reduced for intermediate-term androgen suppression plus zoledronic acid vs short-term androgen suppression (SHR = 0.71, P = .021).
There was also a significant difference among treatments in use of secondary therapeutic intervention (25.6%, 28.9%, 20.7%, and 15.3%; P = .0053), with risk being reduced for intermediate-term androgen suppression plus zoledronic acid vs short-term androgen suppression (SHR = 0.67, P = .024).
Post hoc analyses suggested that reductions in PSA progression and need for secondary therapeutic intervention with intermediate-term androgen suppression plus zoledronic acid were restricted to tumors with Gleason score of 8 to 10 and that intermediate-term androgen suppression was better than short-term androgen suppression in tumors with a Gleason score of ≤ 7 or lower.
The investigators concluded: “Compared with [short-term androgen suppression], [intermediate-term androgen suppression] plus zoledronic acid was more effective for treatment of prostate cancers with a Gleason score of 8-10, and [intermediate-term androgen suppression] alone was effective for tumors with a Gleason score of 7 or lower. Nevertheless, these findings are based on secondary endpoint data and post-hoc analyses and must be regarded cautiously. Long-term follow-up is necessary, as is external validation of the interaction between zoledronic acid and Gleason score.”
James W. Denham, MD, of University of Newcastle, Australia, is the corresponding author for The Lancet Oncology article.
Funding for the study was provided by the National Health and Medical Research Council of Australia, New Zealand Health Research Council, New Zealand Cancer Society, University of Newcastle (Australia), Calvary Health Care, Hunter Medical Research Institute, Maitland Cancer Appeal, Cancer Standards Institute New Zealand, Novartis Pharmaceuticals Australia, and Abbott Pharmaceuticals Australia. For full disclosures of the study authors, visit www.thelancet.com.
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