Ann Arbor, MI—Long-term hormone therapy appears to do more harm than good for many recurrent prostate-cancer patients, according to a new study that recommends that treatment guidelines be reconsidered.

The secondary analysis of a recent clinical trial that changed the standard of care for men with recurring prostate cancer was presented at the 61st Annual Meeting of the American Society for Radiation Oncology in Chicago.

University of Michigan–led researchers suggest that patients’ postoperative prostate-specific antigen (PSA) level be used to determine the need for antiandrogen therapy. Their presentation discussed reanalyzed data from NRG Oncology/RTOG 9601, a randomized, phase III clinical trial initially reported in 2017. The original trial determined that adding 2 years of antiandrogen therapy to postsurgical radiation treatment for men with recurrent prostate cancer increased their long-term overall survival rate.

Based on that, clinical guidelines began to recommend that men with recurrent prostate cancer be treated with both radiation and long-term hormone therapy after surgery. The secondary analysis of this data, which divides patients into those with high and low PSA levels, called that advice into question, however. It found that men with low PSA levels after prostate surgery gained no overall survival benefit from long-term hormone therapy. Even worse, the authors report, the risk of dying from other causes was substantially increased in those patients.

“What we showed for the first time is that a patient’s PSA level is a predictive biomarker,” said Daniel Spratt, MD, Laurie Snow Research Professor of Radiation Oncology and Chair of the Genitourinary Clinical Research Program at the University of Michigan Rogel Cancer Center. “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.”

For the new analysis, the study team reexamined data for 760 patients treated between 1998 and 2003 at more than 100 centers across North America whose cancer returned following surgical removal of the prostate.

In the original study, overall survival rates were compared after patients were randomized to two groups: either postsurgical radiation therapy plus a nonsteroidal antiandrogen (bicalutamide 150 mg/day) or placebo for 2 years.

The secondary analysis, on the other hand, first divided patients into two groups based upon their PSA levels prior to radiation: those with PSA greater than 1.5 ng/mL (n = 118) and those with PSA lower than 1.5 ng/mL (n = 642), which was a stratification factor on the trial.

Both studies found a significant improvement in overall survival rates for patients whose PSA was higher than 1.5 ng/mL (hazard ratio [HR] 0.45 [0.25-0.81]). Yet the re-analysis determined no overall survival benefit for patients with PSA levels lower than 1.5 ng/mL (HR 0.87 [0.66-1.16]).

Dr. Spratt pointed out that, in the past, it had been standard treatment to allow PSA to rise to high levels following radical prostatectomy 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 said.

When researchers further analyzed data for a subset of 389 patients with PSA levels less than or equal to 0.6 ng/mL—which is closer to today’s standard for postsurgical radiation treatment—they found that this group was twice as likely to die from causes other than cancer when hormone therapy was added, with the greatest risk of death (subdistribution HR 4.14 [1.57-10.89]) in the 148 patients with the lowest PSA levels (0.2-0.3 ng/mL).

That subset of patients also was between three to four times more likely to experience a combination of severe cardiac events and neurologic problems (odds ratio 3.57 [1.09-15.97], P = .05).

“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,” Dr. Spratt noted. “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.”

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