In an analysis from the NRG/RTOG 9601 trial reported in JAMA Oncology, Daniel E. Spratt, MD, and colleagues found that higher prostate-specific antigen (PSA) pre–salvage radiotherapy (SRT) levels after prostatectomy were associated with better overall survival vs lower levels in men with prostate cancer receiving long-term antiandrogen therapy.
Daniel E. Spratt, MD
Study Details
In the trial, 760 men with adverse pathologic findings and detectable PSA (0.2–4.0 ng/mL) after radical prostatectomy were randomly assigned between 1998 to 2003 to 2 years of nonsteroidal antiandrogen treatment with bicalutamide at 150 mg/d or placebo—both with SRT. Overall survival at 12 years was 76% in the hormone therapy group vs 71% in the placebo group. However, as noted by the investigators, hormone therapy has associated morbidity, and there currently are no biomarkers to predict which patients may derive greatest benefit from treatment.
The current secondary analysis involved 313 patients treated with placebo and 329 patients treated with bicalutamide with PSA levels ≤ 1.5 ng/mL, and 63 and 65, respectively, with levels > 1.5 ng/mL (the original protocol-specified PSA stratification levels). The analysis included assessment of risk of grade ≥ 3 cardiac and neurologic toxicity, given evidence of association of hormone therapy with these adverse outcomes.
Key Findings
In the PSA > 1.5 ng/mL stratum, the hormone therapy group showed improved overall survival, with an absolute 25% benefit in 12-year overall survival (74% vs 49%; hazard ratio [HR] = 0.45, 95% confidence interval [CI] = 0.25–0.81).
In the PSA ≤ 1.5 ng/mL stratum, no survival benefit was observed for the hormone therapy group, with a 12-year absolute difference of 1% (77% vs 76%; HR = 0.87, 95% CI = 0.66–1.16).
In a subgroup of 253 patients with PSA of 0.61 to 1.5 ng/mL, those in the hormone therapy group had a significant overall survival benefit (HR = 0.61, 95% CI = 0.39–0.94).
In a subgroup of 389 men receiving early SRT (PSA ≤ 0.6 ng/mL), those in the hormone therapy group did not have improved overall survival (HR = 1.16, 95% CI = 0.79–1.70) and exhibited increased risk for other-cause mortality (subdistribution HR = 1.94, 95% CI = 1.17–3.20).
During follow-up, grade ≥ 3 cardiac events were observed in 4.6% of patients in the hormone therapy group vs 1.6% of the placebo group, and grade ≥ 3 neurologic events were observed in 2.1% vs 1.1%. Two patients in the hormone therapy group had grade 5 cardiac events, with unknown causal attribution. Odds ratios for combined grade ≥ 3 cardiac and neurologic events for the hormone therapy vs placebo groups were 2.48 (P = .02) for the entire population, 2.96 (P = .02) in the PSA ≥ 1.5 ng/mL stratum, and 3.57 (P = .05) among those receiving early SRT (PSA levels ≤ 0.6 ng/mL). No significant differences between groups were observed for other grade ≥ 3 toxicities, including late gastrointestinal or genitourinary toxicities.
The investigators concluded, “These results suggest that pre-SRT PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with SRT. In patients receiving late SRT (PSA > 0.6 ng/mL), hormone therapy was associated with improved outcomes. In men receiving early SRT (PSA ≤ 0.6 ng/mL), long-term antiandrogen treatment was not associated with improved overall survival. Future randomized clinical trials are needed to determine hormonal therapy benefit in this population.”
Dr. Spratt, of the Department of Radiation Oncology, University of Michigan, Ann Arbor, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by the Prostate Cancer Foundation, National Institutes of Health, and Department of Defense. For full disclosures of the study authors, visit jamanetwork.com.
