Findings from the randomized phase III NRG Oncology/RTOG 9601 trial were initially reported in 2017, and showed that the addition of 2 years of antiandrogen therapy to postsurgical radiation treatment for men with recurrent prostate cancer increased their long-term overall survival rate. That study led to the recommendation that men with recurrent prostate cancer be treated with both radiation and long-term hormone therapy after surgery. However, a secondary analysis of the trial data, which split patients into two cohorts (those with high and low prostate-specific antigen [PSA] levels), has found that men with low PSA after surgery gained no overall survival benefit from long-term hormone therapy, and that treatment with hormone therapy increased their risk of dying from other causes. These findings were presented by Spratt et al at the 61st Annual Meeting of the American Society for Radiation Oncology (ASTRO) (Abstract LBA1).
“What we showed for the first time is that a patient’s PSA level is a predictive biomarker—that is, you can use a patient’s PSA to better select which men should receive hormone therapy, and to predict who will benefit and who will not benefit from this treatment, and who may actually be harmed by it. We found that the lower the PSA, the more harm the patient experienced. The higher the PSA, the more likely the patient was to benefit from hormone therapy, because it decreased their chances of dying from prostate cancer and resulted in improved overall survival rates,” said first study author Daniel Spratt, MD, of the University of Michigan Rogel Cancer Center.
Secondary Analysis
Dr. Spratt and his team reexamined data for 760 patients treated between 1998 and 2003 at more than 100 centers across North America whose cancer recurred following radical prostatectomy. In the original study, patients were randomly assigned to receive either postsurgical radiation therapy plus a nonsteroidal antiandrogen (bicalutamide 150 mg/day) or placebo for 2 years, and overall survival rates were compared. In this secondary analysis, researchers first divided patients into two groups based upon their PSA levels prior to radiation: those with PSAs greater than 1.5 ng/mL (n = 118) and those with PSAs lower than 1.5 ng/mL (n = 642), which was a stratification factor on the trial. As in the original study, they found a significant improvement in overall survival rates for patients treated with bicalutamide whose PSA was higher than 1.5 ng/mL (hazard ratio [HR] = 0.45 [0.25–0.81]). However, there was no overall survival benefit for men with PSA levels lower than 1.5 ng/mL (HR = 0.87 [0.66–1.16]).
Dr. Spratt said he wanted to reexamine what happened to patients with lower PSA levels in light of changes over the past 2 decades in how recurrent prostate cancer is treated. At the time NRG Oncology/RTOG 9601 was enrolling patients, he said, it was standard to allow PSA to rise to high levels following radical prostatectomies before initiating radiation therapy, but that’s no longer the case. “The current standard is that, after surgery, if the PSA becomes detectable at very low levels—the lower the better—we recommend giving radiation,” he explained.
“What we showed for the first time is that a patient’s PSA level is a predictive biomarker—that is, you can use a patient’s PSA to better select which men should receive hormone therapy, and to predict who will benefit and who will not benefit from this treatment, and who may actually be harmed by it. We found that the lower the PSA, the more harm the patient experienced. The higher the PSA, the more likely the patient was to benefit from hormone therapy, because it decreased their chances of dying from prostate cancer and resulted in improved overall survival rates."— Daniel Spratt, MD
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Lower PSA Level Results
The researchers further analyzed data for a subset of patients with PSA levels less than or equal to 0.6 ng/mL (n = 389), closer to today’s standard for postsurgical radiation treatment. They found that this group was more likely to die from causes other than cancer when treated with hormone therapy plus radiation (subdistribution HR [sHR] = 1.94 [1.17–3.20]). Men with the lowest PSA levels (0.2–0.3 ng/mL, n=148) had the greatest risk of death (sHR = 4.14 [1.57-10.89]). This subset of patients was also more likely to experience grade 3–5 cardiac events and neurological problems (P = .05) when treated with hormone therapy.
The authors concluded, “Pre–salvage radiotherapy PSA is both a prognostic and true predictive biomarker for benefit of hormone therapy with salvage radiotherapy. Long-term antiandrogen therapy did not improve overall survival in patients receiving early salvage radiotherapy and may increase other-cause mortality. Ongoing trials are enrolling to identify which patients receiving early salvage radiotherapy will benefit from hormone therapy.”
Clinical Relevance
“We went into this study expecting that men with low PSAs probably would derive minimal benefit from hormone therapy, but we were surprised at the magnitude of harm that these patients experienced,” said Dr. Spratt. “A lot of these side effects have been reported over the past few decades, but demonstrating this in a clinical trial to this extent has not been done before.”
Based on these findings, Dr. Spratt said he believes clinical guidelines for treating men with recurrent prostate cancer should be reconsidered. “For post-operative patients with low PSAs, they do very well with just radiation therapy after surgery. They actually have very good long-term outcomes. Patients with high PSAs, over 1.5 ng/mL, should continue to receive long-term hormone therapy in addition to radiation. It improves their survival substantially. But for patients with PSAs below 0.6 ng/mL who receive postoperative radiation therapy, there needs to be a real discussion about the fact that hormone therapy has not been shown to help these men live longer. Our study shows that long-term hormone therapy could actually hurt their survival and cause them other problems. A lot of shared decision-making is needed before recommending hormone therapy to all men with low PSAs.”
Dr. Spratt and his colleagues are currently enrolling postoperative patients with prostate cancer in another study that will delve deeper into who might benefit from hormone therapy and who might not based on genetic testing of their tumors (BALANCE trial/NRG GU-006).
Disclosure: For full disclosures of the study authors, visit astro.org.
