Long-Term Hormone Therapy May Harm Prostate Cancer Subset

Roxanne Nelson, RN, BSN

September 17, 2019

CHICAGO — It may be time to revisit clinical guidelines for a subset of patients with prostate cancer, say researchers.

Current guidelines recommend all men be offered hormone therapy when receiving salvage radiotherapy (SRT) following prostate cancer surgery and subsequent biochemical recurrence.

But a new, secondary analysis of a major clinical trial in this setting now indicates that one treatment plan may not fit all.

"Our data demonstrate that men with lower PSAs are more harmed then helped by long-term hormone therapy," said lead author Daniel Spratt, MD, an associate professor of radiation oncology and chair of the Genitourinary Clinical Research program at the University of Michigan Rogel Cancer Center, Ann Arbor.

Initial findings from this major trial — NRG Oncology/RTOG 9601 — found that adding 2 years of anti-androgen therapy to postoperative radiation therapy in patients with recurrent disease increased overall long term survival. The results of that study led to the recommendation that this population should be treated with both radiation and long-term hormone therapy after surgery.

However, the new subset analysis of these data shows that men with low PSA levels after prostate surgery gained no overall survival benefit from long-term hormone therapy and, in fact, it greatly increased their risk of dying from other causes.

Patients with PSA levels less than or equal to 0.6 ng/mL were twice as likely to die from causes other than cancer when hormone therapy was added to their treatment regimen, and the greatest mortality risk was among those with the lowest PSA levels (0.2-0.3 ng/mL).

This subset was also between three and four times more likely to experience a combination of severe cardiac events and neurologic problems.

"What we showed for the first time is that a patient's PSA level is a predictive biomarker," said Spratt, who presented the study results here at a plenary session of the American Society for Radiation Oncology (ASTRO) annual meeting. "PSA prior to salvage radiotherapy predicts who will benefit most from hormone therapy."

"Guidelines should change to reflect this finding," he emphasized.

Guidelines should change to reflect this finding. Dr Daniel Spratt

Changing Times

Hormone therapy is associated with well-documented adverse events, including cardiac effects, and an overall survival benefit from hormone therapy has not been seen among patients treated with early SRT.

Thus, the current analysis was conducted to determine if the pre-SRT PSA can serve as both a prognostic and predictive biomarker of benefit or harm from anti-androgen therapy.

Spratt also emphasized that 20 years ago, when this study was first enrolling, it was standard to allow postoperative PSA levels to rise to high levels before initiating radiation therapy, but protocols have now changed. Currently, the standard of care is to begin radiation therapy if PSA levels becomes detectable at very low levels.

The NRG Oncology/RTOG 9601 was a randomized, phase III clinical trial that included 760 men with a median follow up of 13 years. The patients were treated between 1998 and 2003 at more than 100 centers and, in the original study, were randomly assigned to either postoperative radiation therapy plus a nonsteroidal anti-androgen (bicalutamide 150 mg/day) or placebo for 2 years.

Harm Seen With Low PSA

In their secondary analysis, Spratt and colleagues divided the cohort into two groups based on PSA levels prior to receiving radiation therapy: PSAs greater than 1.5 ng/mL (n = 118) and PSAs lower than 1.5 ng/mL (n = 642).

The interaction between PSA level and hormone therapy benefit for overall survival was significant (P = .02). Similar to the initial analysis, they found overall survival was significantly improved in the patient cohort with PSA levels greater than 1.5 ng/mL (hazard ratio [HR], 0.45).

However, no overall survival benefit was observed for patients with PSA levels lower than 1.5 ng/mL (HR, 0.87).

A further analysis was conducted for the subset of patients with PSA levels 0.6 ng/mL or lower (n = 389), which is similar to the current standard for initiating postoperative radiation treatment. In this group, men with a pre-SRT PSA ≤0.6 ng/mL had a higher other cause mortality (HR, 1.94) from bicalutamide, and this effect was greatest in those with a PSA of 0.2-0.3 ng/ml (n = 148; HR, 4.14).

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

In the group with the lowest PSA levels, 12-year estimates for other cause mortality were 10% in the placebo group vs 19% in those treated with bicalutamide (HR, 1.94; P = .009), and were 3 to 4 times more likely to experience a combination of severe cardiac events and neurologic problems (OR, 3.57; P = .05).

"We have now 3 randomized trials with over 2400 men total that do not demonstrate that short- or long-term hormone therapy improves overall survival in men receiving early salvage radiotherapy at low PSAs," said Spratt.

The researchers are currently enrolling similar patients in another study that will further analyze who might derive the most benefit from hormone therapy and who might not, using genetic testing (BALANCE trial/NRG GU-006).

Proof of Burden

In a discussion of the study, Paul Nguyen, MD, vice-chair for clinical research radiation oncology at Brigham and Women's Hospital and associate professor at Harvard Medical School, Boston, Massachusetts, emphasized that this is an important reanalysis of an important study, but that it also poses the question of how to treat a patient with a PSA of 0.6 or less.

"And there are arguments on both sides," he explained. "For the argument against, it is basically a burden of proof argument."

Hormone therapy is toxic and impacts quality of life, Nguyen said, so the "burden is on those who want to use hormone therapy to be absolutely sure that there is a survival benefit for every patient before offering them this drug."

"And based on the data from the study, for patients with a PSA of 0.2 to 0.6, the data are not so encouraging," Nguyen said.

There is also a burden of proof on those who argue in favor of hormone therapy. "This trial did show an overall survival benefit," Nguyen noted, "and that means the burden of proof is on you to be absolutely certain that the patient is not going to have a survival benefit before you withhold the therapy."

He also pointed out that androgen deprivation therapy (ADT) advocates can argue that the subgroup analysis is hypothesis-generating rather than absolute proof of lack of benefit. "And once you start diving into subgroups, they are not necessarily all powered for overall survival," Nguyen noted.

Nguyen explained that, based on the evidence, patients with a PSA greater than 0.6 ng/mL should receive ADT with salvage radiation due to the evidence of a survival benefit.

"For those with a PSA of 0.6 or less, depending on your view of who has the burden of proof, I think physicians can reasonably disagree on whether ADT should be offered," he concluded. "In my view, it is best to offer ADT to select patients based on Gleason score, PSA kinetics, stage, margins, genomics and life expectancy."

Experts Weight In

Two other experts approached by Medscape Medical News also offered their views on the study.

This subset analysis provides compelling evidence of the benefit of adding ADT to external beam radiation therapy following a PSA recurrence after primary treatment with radical prostatectomy for some patients, commented Eric M. Horwitz, MD, chair of radiation oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania.

"However, the authors of this study add to our knowledge by demonstrating which patients benefit for the additional treatment — those with PSA levels >1.5 ng/mL," he said. "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 anti-androgen therapy to postsurgical radiation treatment for men increased their long-term overall survival rate." 

Horwitz pointed out that in the more than two decades since the start of this study, there has been a recognition of the toxicity of hormones in addition to their benefit, and this current analysis shows which patients will benefit the most from hormone therapy.

"They demonstrated that long-term anti-androgen therapy did not improve overall survival in patients receiving early salvage radiation therapy, and may increase other cause mortality," he added. "In addition to this subset analysis of NRG Oncology/RTOG 9601, results from NRG Oncology/RTOG 0534 and NRG Oncology GU006 will further help establish the standard of care for men with PSA recurrences following primary prostate surgery."

Anthony Zietman, MD, director of the Harvard Radiation Oncology Residency program and the GU Service at Massachusetts General Hospital in Boston, noted that "we do a lot of randomized trials in our specialty, and they really do define the care for our patients. But sometimes it's the second analyses of these studies that really allows us to fine-tune and personalize the recommendations that come out of the trial."

He added: "Sometimes we find that there is a big benefit for many, and a decrement for some, and it's the secondary analyses that brings this out."

About 100,000 men or so per year have a radical prostatectomy for prostate cancer, and of that group, about 30,000 have a rising PSA which indicates that the cancer may be recurring. "The vast majority of them will go on to receive radiation therapy, and based on the earlier results of this study, we will give them hormone therapy," Zietman said. "These results suggest that maybe we should hold back a little, as there are some men who will benefit, some who won't benefit, and some who might be harmed."

"I think we can be more thoughtful and cautious," Zietman noted, adding that from here on, "I am going to be more cautious with my own patients."

Spratt is an employee at the University of Michigan and has declared relationships with Janssen and Blue Earth. Zeitman and Horwitz have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2019 Annual Meeting:  Abstract LBA-1. Presented September 16, 2019

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