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Low PSA levels predict lack of benefit from long-term hormone therapy after prostate surgery
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Long-term antiandrogen therapy did not improve OS when administered during early salvage radiation therapy among patients with recurrent prostate cancer and low PSA scores, according to results of a secondary analysis from the randomized phase 3 NRG Oncology/RTOG9601 study presented during the plenary session of American Society of Radiation Oncology Annual Meeting.
Further, results showed the hormone therapy may increase the risk for mortality from other causes.
Original results from the trial — published in 2017 in The New England Journal of Medicine — showed the addition of long-term antiandrogen therapy to salvage radiation therapy improved OS among men with recurrent prostate cancer. Those findings led to the recommendation that these men should receive 2 years of antiandrogen therapy postsurgical radiation.
That recommendation should now be reconsidered, researchers noted.
“What we showed for the first time is that a patient’s PSA level is a predictive biomarker,” Daniel Spratt, MD, professor of oncology and chair of the genitourinary clinical research program at University of Michigan Rogel Cancer Center, said in a press release. “We found that lower 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 OS rates.”
Because hormone therapy is associated with adverse events, especially cardiac events, and because there is a lack of evidence supporting an OS benefit from hormone therapy for men treated with early salvage radiation therapy, Spratt and colleagues conducted a secondary analysis of RTOG9601 to evaluate whether pre-salvage radiation therapy PSA levels can serve as prognostic and predictive biomarkers of benefit from hormone therapy.
Researchers re-examined data from 760 men with PSA scores ranging from 0.2 ng/mL to 4 ng/mL who had been randomly assigned to receive either salvage radiation therapy in combination with bicalutamide at 150 mg daily or placebo for 2 years between 1998 and 2003.
Spratt and colleagues stratified patients by entry PSA score, with 642 men in the low group (0.2-1.5 ng/mL) and 118 in the high group (>1.5-4 ng/mL).
OS served as the primary endpoint. Distant metastasis and other-cause mortality served as secondary endpoints.
Results showed no significant OS benefit with bicalutamide in patients with PSA of 1.5 ng/mL or lower who received bicalutamide (HR = 0.87; 95% CI, 0.66-1.16).
Men with PSA greater than 1.5 ng/mL, however, demonstrated significantly improved OS with bicalutamide, consistent with the earlier findings from the study (HR = 0.45; 95% CI, 0.25-0.81).
At the time the original study was conducted, standard practice was to allow PSA to rise to high levels following radical prostatectomies before initiating radiation therapy. However, standard practice dictates that early radiation is given if men present with low PSA levels after surgery.
For that reason, Spratt and colleagues further evaluated a subset of 389 patients with PSA levels of 0.6 ng/mL or lower, which is closer to today’s standard for postsurgical radiation.
In this group, researchers observed increased rates of other-cause mortality among those treated with bicalutamide (subdistribution HR [sHR] = 1.94; 95% CI, 1.17-3.20), particularly if the PSA score was 0.2 ng/mL to 0.3 ng/mL (n = 148; sHR = 4.14; 95% CI, 1.57-10.89).
Researchers also observed increased rates of grade 3 to grade 5 cardiac and neurologic events in this subset of patients.
“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,” Spratt said. “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.
“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,” he added. “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.” – by John DeRosier
Reference:
Spratt DE, et al. Abstract LBA1. Presented at: ASTRO Annual Meeting; Sept. 15-18, 2019; Chicago.
Disclosures: Spratt reports research funding from or consulting roles with Blue Earth and Janssen. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Eric M. Horwitz, MD, FABS, FASTRO
The subset analysis of the NRG Oncology/RTOG 9601 randomized phase 3 trial provides compelling evidence of the benefit of adding androgen deprivation therapy to external beam radiation therapy following a PSA recurrence after primary treatment with radical prostatectomy for some patients. However, the authors of this study add to our knowledge by demonstrating which patients benefit from the additional treatment (those with PSA levels > 1.5 ng/mL). Until the presentation and publication of the results of NRG Oncology/RTOG 9601, ADT was not part of the standard of care in the treatment of men who experienced PSA recurrences following prostatectomy. This landmark study showed that adding 2 years of antiandrogen therapy to postsurgical radiation treatment for men increased their long-term OS rate.
In 2018, results of NRG Oncology/RTOG 0534 also demonstrated a benefit to combining ADT with post-prostatectomy surgery. Differences in these two studies included the length of time for the ADT (2 years vs. 6 months) as well as the radiation technique.
In the more than 2 decades since the start of RTOG 9601, there has also been a recognition of the toxicity of hormones in addition to their benefit. What Spratt and colleagues have demonstrated with this valuable subset analysis is which patients benefit most from the addition of ADT. They also demonstrated that long-term antiandrogen therapy did not improve OS in patients receiving early salvage radiation therapy and may increase other-cause mortality.
In addition to this subset analysis of NRG Oncology/RTOG 9601, results from NRG Oncology/RTOG 0534 and NRG Oncology GU006 with further help establish the standard of care for men with PSA recurrences following primary prostate surgery.
Reference:
Pollack A, et al. Int J Radiat Oncol Biol Phys. 2018;doi:10.1016/j.ijrobp.2018.08.052.
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