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Consider PSA Before Adding ADT to Salvage Radiation

— Men with levels below 0.6 ng/mL show no benefit, at risk of other-cause mortality

Ƶ MedicalToday

CHICAGO -- Prostate cancer patients undergoing salvage radiotherapy with the lowest prostate-specific antigen (PSA) levels derived no survival benefit and may be harmed by the addition of hormonal therapy, a secondary analysis of the RTOG 9601 trial found.

Among 389 patients with a PSA of 0.6 ng/mL or less, no overall survival benefit was seen for those randomized to androgen deprivation therapy (ADT), and these men had a twofold higher chance of death from causes other than their disease (HR 1.94, 95% CI 1.17-3.20), reported Daniel Spratt, MD, of the University of Michigan in Ann Arbor.

At 12 years, 19% of men treated with ADT died from causes other than prostate cancer versus 10% of those given placebo, according to the findings presented here at the 2019 American Society for Radiation Oncology meeting.

"Guidelines recommend that all men be offered hormone therapy when receiving salvage radiation therapy. However, our data demonstrate that men with lower PSAs are actually probably more harmed than helped by long-term hormone therapy," Spratt said during a press briefing.

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Daniel Spratt, MD, presenting the findings at ASTRO

In the 148 men with the lowest PSA levels (0.2-0.3 ng/mL), death from other causes was fourfold higher in the ADT group (HR 4.14 95% CI 1.57-10.89), and these patients experienced a higher likelihood of severe cardiac or neurological adverse events (OR 3.57, 95% CI 1.09-15.97, P=0.05).

Multiple trials have now failed to show an overall survival benefit with short- or long-term hormonal therapy in men with low PSA levels, Spratt explained. "Thus, PSA prior to salvage radiation actually is not only prognostic, it predicts who will benefit most from hormone therapy, and guidelines should now be updated to reflect this finding."

NRG Oncology/RTOG 9601 was a practice-changing phase III trial that from 1998 to 2003 randomized 760 men undergoing post-prostatectomy radiation therapy to 2 years of daily ADT -- bicalutamide (Casodex) -- or placebo. Participants had PSA levels ranging from 0.2-4.0 ng/mL.

The original analysis, reported in 2016, showed a 12-year overall survival rate of 76.3% with bicalutamide versus 71.3% with placebo (HR 0.77, 95% CI 0.59-0.99, P=0.04), driven largely by those with the highest PSAs.

But for multiple reasons the findings were "never fully embraced," Eric Horwitz, MD, of Fox Chase Cancer Center in Philadelphia, told Ƶ. The trial was old and the selected hormone regimen was no longer being used.

Yet still, it was the first study to show that ADT could benefit patients undergoing salvage radiation, he said. Findings from SPPORT, which were presented at last year's ASTRO meeting and tested shorter duration ADT (6 months), changed opinions and helped usher hormonal therapy into clinical practice in this setting. "It's definitely fewer side effects when you give somebody a medicine for 6 months versus 2 years," Horwitz said, noting that in RTOG 9601 bicalutamide was given at a toxicity-prone dose of 150 mg.

"It actually has a lot of side effects, and the dose is higher than what's done now," he said.

Finally, when the trial was enrolling, it was standard to allow PSA to rise to higher levels before starting radiation; today urologists typically refer patients before their post-prostatectomy PSA levels reach 0.2 ng/mL.

For this reason, Spratt's group sought to reanalyze the RTOG 9601 findings with more modern PSA cutoffs, focusing on the 85% of patients that fell into the 0.2-1.5 ng/mL range, a prespecified stratification variable of the trial. At 12 years, there was no significant survival difference between bicalutamide and placebo for patients with PSAs in this range (77% vs 76%, respectively; P=0.36).

They also examined outcomes by the trial's median PSA (0.6 ng/mL) and the median PSAs of the more contemporary GETUG-16 and SPPORT trials (0.2-0.3 ng/mL).

"Above 0.6, there's a survival benefit consistent with the overall trial," Spratt told Ƶ. "So I think that we would need more data to withhold hormone therapy in those patients."

For patients in the 0.5-0.6 ng/mL range, "They're the ones who I would say, 'It's not wrong to have hormones, but you definitely don't have to do hormones,'" said Horwitz.

No overall survival benefit with ADT was seen below this cutoff, however, and interaction testing showed a trend toward harm at the lowest PSA levels (P for interaction=0.02):

  • >1.5 ng/mL (HR 0.45, 95% CI 0.25-0.81)
  • >0.6-1.5 ng/mL (HR 0.61, 95% CI 0.39-0.94)
  • >0.3-0.6 ng/mL (HR 0.94, 95% CI 0.59-1.50)
  • 0.2-0.3 ng/mL (HR 1.78, 95% CI 0.88-3.57)

And while distant metastasis-free survival was improved in the group with the highest PSA, no benefit was seen for patients with the lowest levels (P for interaction=0.03).

"We now know there's a certain group of men who do benefit from the combination of hormones plus radiation for a PSA recurrence after surgery, but it's still not everybody," Horwitz said.

Disclosures

Spratt disclosed financial relationships with Janssen and Blue Earth.

Primary Source

American Society for Radiation Oncology

Spratt DE, et al "Two years of anti-androgen treatment increases other-cause mortality in men receiving early salvage radiotherapy: A secondary analysis of the NRG Oncology/RTOG 9601 randomized phase III trial" ASTRO 2019; Abstract LBA1.