Robert T. Dess, MD

In an analysis from the NRG/RTOG 9601 trial reported in JAMA Oncology,¹Robert T. Dess, MD, of the Department of Radiation Oncology, University of Michigan, Ann Arbor, and colleagues found that men with higher prostate-specific antigen (PSA) presalvage radiotherapy levels after prostatectomy had a larger relative response to antiandrogen treatment for prostate cancer vs those with lower pretreatment PSA levels. The findings suggest presalvage radiotherapy PSA levels may serve as a biomarker for identifying which patients may benefit most from hormone therapy and which may avoid hormone therapy and its associated adverse effects.

Study Details

In the trial, 760 men with adverse pathologic findings and detectable PSA levels (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 presalvage radiotherapy. 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 the greatest benefit from treatment.

The current secondary analysis involved 313 patients who received placebo and 329 patients who received bicalutamide and had PSA levels ≤ 1.5 ng/mL, as well as 63 and 65 patients with levels > 1.5 ng/mL (the original protocol–specified PSA stratification levels). Analysis included assessment of overall survival, distant metastasis, and other-cause mortality according to PSA level and treatment group. Other-cause mortality was defined as death not meeting any of the following criteria: death due to prostate cancer or complications of study treatment; death with known progressive metastatic disease while on salvage hormone therapy; or death with a known rising PSA level while on salvage hormone therapy. Analysis also included assessment of risk of grade ≥ 3 cardiac and neurologic toxicity, given evidence of association of hormone therapy with these adverse outcomes.

Key Findings

The median follow-up for surviving patients was 13 years. In the PSA level > 1.5 ng/mL stratum, the hormone-therapy group had significantly improved overall survival vs placebo, with an absolute 25% benefit in 12-year overall survival (74% vs 49%; hazard ratio [HR] = 0.45, 95% CI = 0.25–0.81, P = .01; HR = 0.50, P = .03 on multivariate analysis). In this stratum, hormone therapy was also associated with a reduced risk of distant metastasis (stratified HR = 0.36, 95% CI = 0.15–0.84, P = .02; stratified HR = 0.35, P = .03 on multivariate analysis).

In the PSA level ≤ 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, P = .36; HR = 0.86, P = .32 on multivariate analysis). In this stratum, bicalutamide treatment was associated with a nonsignificantly reduced risk for distant metastasis (subdistribution HR = 0.72, 95% CI = 0.51–1.01, P = .06), with the benefit being significant on multivariate analysis (subdistribution HR = 0.67, P = .03).

An interaction test between presalvage radiotherapy PSA level as a continuous variable and hormone therapy treatment effect was significant for both overall survival (HR = 0.69, P = .02) and distant metastasis (HR = 0.68, P = .03), indicating the hormone therapy treatment effect significantly varied according to presalvage radiotherapy PSA level. This interaction remained significant in analysis adjusting for age, Gleason score, T stage, surgical margin, and nadir PSA level.

In a subgroup of 253 patients with a PSA level of between 0.61 and 1.5 ng/mL, those who received hormone therapy had a significant overall survival benefit (HR = 0.61, 95% CI = 0.39–0.94, P = .02). Patients who received hormone therapy also had a reduction in risk for distant metastasis that did not reach statistical significance (HR = 0.69, 95% CI = 0.43–1.12, P = .14).

In a subgroup of 389 men receiving early radiotherapy (PSA level ≤ 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, P = .46) and exhibited an increased risk for other-cause mortality (stratified HR = 1.94, 95% CI = 1.17–3.20, P = .01). The estimated increase in incidence of other-cause mortality in the bicalutamide group was 9.4% at 12 years. The greatest difference in risk of other-cause mortality in the hormone-therapy group was observed among 148 men with PSA levels between 0.2 and 0.3 ng/mL (stratified HR = 4.14, 95% CI = 1.57–10.9, P = .003).

During follow-up, grade ≥ 3 cardiac events were observed in 4.6% of 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 level ≥ 1.5 ng/mL stratum, and 3.57 (P = .05) among those receiving early radiotherapy (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 observed: “The RTOG 9601 trial has the longest follow-up of any randomized clinical trial of presalvage radiotherapy with or without hormone therapy. We found that not only was there an increase in combined cardiac and neurologic grades 3 to 5 events, but there was also an increased risk of [other-cause mortality] in those assigned to early radiotherapy with antiandrogen therapy. Although this may be specific to high-dose, long-term antiandrogen treatment (150 mg of bicalutamide), [luteinizing hormone-releasing hormone] agonist treatments have also been associated with cardiac events, dementia, metabolic syndrome, and fracture risk…. In men receiving early radiotherapy, a population that appears to derive minimal oncologic benefit from hormone therapy, the morbidity of long-term antiandrogen treatment may have been more apparent given the mature follow-up of the RTOG 9601 trial.”

They concluded: “These results suggest that presalvage radiotherapy PSA level may be a prognostic biomarker for outcomes of antiandrogen treatment with presalvage radiotherapy. In patients receiving late presalvage radiotherapy (PSA level > 0.6 ng/mL), hormone therapy was associated with improved outcomes. In men receiving early presalvage radiotherapy (PSA level ≤ 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.” 

Publisher's Note: This article was originally published in the June 10, 2020 issue of The ASCO Post.

DISCLOSURE: The study was supported by the Prostate Cancer Foundation, the National Institutes of Health, and the Department of Defense. For full disclosures of study authors, visit jamanetwork.com.

REFERENCE

1. Dess RT, Sun Y, Jackson WC, et al: Association of presalvage radiotherapy PSA levels after prostatectomy with outcomes of long-term antiandrogen therapy in men with prostate cancer. JAMA Oncol 6:1-9, 2020.