Prostate Cancer Subgroup May Benefit From Intensified Therapy

Roxanne Nelson, RN, BSN

February 27, 2023

SAN FRANCISCO — For patients with prostate cancer who have unfavorable features and a detectable PSA following a radical prostatectomy, the standard of care is treatment with 6 months of a GnRH agonist with salvage radiation therapy (SRT), as established by the GETUG-16 trial (Lancet Oncol. 2016;17:747-756).

A new trial, dubbed FORMULA-509, explored whether outcomes could be improved by intensifying the drug treatment by adding 6 months of abiraterone acetate plus prednisone as well as apalutamide on top of the GnRH agonist alongside the salvage radiotherapy.

This approach did not provide a significant improvement in progression-free survival (PFS) or metastasis-free survival (MFS) in the overall study population.

However, the combination did significantly improve PFS and MFS in a subset of men with PSA levels greater than 0.5 ng/mL.

"Although this primary analysis did not meet the prespecified threshold for statistical significance, it does strongly suggest that the addition of abiraterone acetate/prednisone/apalutamide to salvage radiotherapy plus 6 months of ADT [androgen deprivation therapy] may improve progression-free survival and metastasis-free survival," said lead author Paul L. Nguyen, MD, of the Dana-Farber Cancer Institute in Boston and a professor of radiation oncology at Harvard Medical School.

"This may be particularly evident in the subgroup of patients with PSA greater that 0.5 ng/mL where a pre-planned subgroup analysis by stratification factors observed a statistically significant benefit for both progression-free survival and metastasis-free survival," he said. "Six months of intensified ADT with next generation anti-androgens may provide an attractive alternative to lengthening ADT for patients with rising PSA and unfavorable features after radical prostatectomy."

The study results were presented here at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Benefit in Subset

The FORMULA-509 trial included 305 patients with PSA ≥0.1 ng/mL who had undergone a radical prostatectomy, and who had one or more unfavorable risk features (Gleason 8-10 disease, PSA >0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative margins, persistent PSA, gross local/regional disease).

"This was a pretty high-risk population," Nguyen emphasized, as 35% had Gleason score of 9, about a third (31%) a PSA >0.5, and 29% were pathologic node positive.

All patients received salvage radiotherapy plus 6 months of GnRH agonist (bicalutamide 50 mg), and half were randomly assigned to also receive abiraterone acetate/prednisone 1000 mg/5 mg + apalutamide 240 mg daily.

At a median follow-up of 34 months, the 3-year PFS rate was 74.9% in the AAP-apalutamide arm vs 68.5% for the control group (hazard ratio [HR], 0.71; P = .06), and the 3-year MFS rate was 90.6% vs 87.2%, respectively (HR, 0.57; P = .05).

In the subset of patients with a PSA greater than 0.5 ng/mL, the 3-year PFS and MFS rates were significantly higher with in the AAP-apalutamide group: the 3-year PFS rate was 67.2% vs 46.8% (HR, 0.50; P = .03), and the 3-year MFS rate was 84.3% vs 66.1% (HR, 0.32; P = .02).

Adverse events were consistent with the known safety profiles of the agents being studied, Nguyen noted. The most common toxicities for AAP-apalutamide vs controls were hypertension (21.8% vs 13.3%), maculopapular rash (11.5% vs 0.6%), diarrhea (8.5% vs 4.8%), and fatigue (7.9% vs 6.1%).

Nguyen noted that even though "we're not supposed to compare clinical trials," the results of this study appeared to compare favorably with those of another trial, the RADICALS-HD, which was presented at the 2022 European Society of Medical Oncology Congress. That study showed that in patients undergoing postoperative radiation therapy, 24 months of ADT was superior to 6 months of ADT in improving both time to salvage ADT and MFS.

However, Nguyen emphasized that it would have to be formally tested, to see if "FORMULA-509 is performing in the ballpark of what 24 months of ADT would do."

"And I think that compared to 6 months of ADT, we can say it is certainly performing in the ballpark," he said. "So, for patients with higher risk features, intensifying 6 months of ADT, I think, may be an appealing alternative to lengthening the ADT duration to 24 months."

He added that this concept would be formally tested in the upcoming PROSTATE IQ study.

Strong Evidence, Standardization Needed

In a discussion of the paper, Tyler Seibert, MD, PhD, of the University of California San Diego, commented that "escalation by 24 months has the strongest evidence today, specifically from the RADICALS-HD trial, with more than 1500 men with 10 years of  follow-up and a clear statistically significant result.

"Intensification for 6 months is a very compelling concept, as most patients are not getting two years of androgen deprivation therapy at this point post-prostatectomy," he continued. "While we await the long term follow-up of this study and the pending PROSTATE IQ trial, and if only 6 months of therapy is acceptable or feasible, the FORMULA-509 [trial] provides convincing evidence that select patients would benefit from intensification with AAP and apalutamide."

Another expert weighed in on the data. Approached by Medscape Medical News for an independent comment, Jeff M. Michalski, MD, MBA, professor of radiation oncology at Washington University, St Louis, Missouri, and president of the American Society of Radiation Oncology, noted a few issues in the study.

He explained that standards had changed since this study was first approved and had begun accrual several years ago. "In context of today's era, the current standard is to do a PET scan if patients have a chemical failure after surgery," he said. "The PSA levels of patients who were treated [in this trial] were very high, and many patients do not want to wait until they reach that level."

Michalski also pointed out the number of patients getting radiation was less that the number who had node-positive disease. "This shows that patients had received suboptimal therapy late in the disease," he said.

Overall, most patients in the study did not receive lymph node radiation, even though they had high-risk features. "A recent study of almost 1800 patients that was published in The Lancet found that there is a benefit to pelvic lymph node radiation," he said. "Because it wasn't mandated, most of the patients did not receive pelvic lymph node radiation, which we now understand offers some benefit."

The reasons for not giving pelvic radiation to these men is unclear. "Treatment was left at the discretion of the physician and this could create bias," Michalski said. "It could drive one arm more than another."

The study also wasn't controlled for pelvic radiation. "Most of the nodal positive patients received it, but the other patients were undertreated," he noted.

Michalski added that he hopes that in the forthcoming PROSTATE IQ study, lymph node radiation and imaging are standardized.

The trial was supported by Janssen Oncology. Nguyen disclosed relationships with, and/or support from, Volatilyx, Bayer, Blue Earth Diagnostics, Boston Scientific, Janssen Oncology, Myovant Sciences, Astellas Pharma, and Janssen. Seibert disclosed relationships with, and/or support from, CorTechs Labs, Varian Medical Systems, and GE Healthcare.

2023 Genitourinary Cancers Symposium: Abstract 303. Presented February 16, 2023

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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