Intensified Drug Regimen Added to Standard of Care Improves Outcomes in Subset of Patients With High-Risk Prostate Cancer

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In the phase III FORMULA-509 trial, the addition of abiraterone acetate/prednisone and apalutamide—compared with bicalutamide—to salvage radiation therapy plus 6 months of treatment with a gonadotropin-releasing hormone (GnRH) agonist failed to improve progression-free survival postprostatectomy in the overall population of patients with unfavorable-risk prostate cancer and detectable prostate-specific antigen (PSA). However, this combination regimen with radiation did achieve meaningfully improved outcomes in a subgroup of patients with a PSA level > 0.5 ng/mL at baseline and should be considered a treatment option for patients at high risk who meet that criterion, according to lead author Paul L. Nguyen, MD, of Dana-Farber Cancer Institute, and colleagues, who presented these findings at the 2023 ASCO Genitourinary Cancers Symposium (Abstract 303).

Methodology and Key Findings

All patients in the trial received salvage radiation therapy and 6 months of androgen-deprivation therapy (ADT) with a GnRH agonist. Patients were then randomly assigned to receive concurrent bicalutamide at 50 mg or abiraterone acetate/prednisone at 1,000 mg/5 mg plus apalutamide at 240 mg daily for 6 months. Radiation to pelvic nodes was required for patients with one positive lymph node (pN1) and optional for lymph node–negative patients (pN0). Stratification factors were PSA > 0.5 ng/mL vs < 0.5 ng/mL and pN0 vs pN1.

In the overall trial, the 3-year progression-free survival rate was 74.9% in the abiraterone acetate/prednisone–plus-apalutamide arm vs 68.5% in the bicalutamide arm (P = .06). The 3-year metastasis-free survival rate was 90.6% vs 87.2%, respectively (P = .05).

In a preplanned subgroup analysis of patients with a baseline PSA > 0.5 ng/mL, the 3-year progression-free survival rates were 67.2% vs 46%, respectively (P = .03). The 3-year metastasis-free survival rates were 84.3% vs 66.1%, respectively (P = .02). The number needed to treat to achieve this benefit was 5.

“There was no benefit [for intensification of therapy] in patients with baseline PSA < 0.5 ng/mL. Although the study did not meet its prespecified threshold for statistical significance in the overall population, the results do strongly suggest that the addition of abiraterone acetate/prednisone plus apalutamide to salvage radiation therapy plus 6 months of ADT may improve progression-free survival and metastasis-free survival. The big finding of the FORMULA-509 trial is that this intensified regimen improved metastasis-free survival in a preplanned analysis of the subgroup of 100 patients with a PSA > 0.5 ng/mL at baseline. The absolute improvement in metastasis-free survival at 3 years was about 18%, favoring the experimental arm,” stated Dr. Nguyen.  

Paul L. Nguyen, MD

Paul L. Nguyen, MD

According to Dr. Nguyen, “The results are relevant for a patient who is getting salvage radiation for a rising PSA postprostatectomy, and the PSA is > 0.5 ng/mL, and you want to give that patient more than 6 months of hormones. Your options are to lengthen the duration of ADT to 24 months, or what FORMULA-509 suggests is that you can also intensify by keeping the duration of 6 months of ADT and adding abiraterone and apalutamide. This is an attractive option for patients in whom you need to intensify treatment beyond 6 months of regular ADT.”

FORMULA-509 is the first formal study of this intensified regimen, he noted.

Additional FORMULA-509 Details

As Dr. Nguyen explained, 6 months of a GnRH agonist plus salvage radiation therapy is the standard of care for patients with prostate cancer and unfavorable features plus a detectable PSA post–radical prostatectomy. The FORMULA-509 trial was designed to evaluate whether adding 6 months of abiraterone acetate/prednisone and apalutamide to this regimen could improve outcomes. 

The FORMULA-509 trial is an investigator-initiated, multicenter, open-label, randomized trial that enrolled 332 evaluable patients from nine sites with unfavorable risk factors postprostatectomy (ie, PSA ≥ 0.1 ng/mL post–radical prostatectomy and one or more of the following unfavorable features: Gleason score 8–10, PSA > 0.5 ng/mL, pT3/T4, pN1 or radiographic N1, PSA doubling time < 10 months, negative surgical margins, persistent PSA, gross local/regional disease, or high-risk Decipher score).

At baseline, the median age was 65 years; 35% of patients had a Gleason score of 9; median PSA was 0.3 mg/mL; 31% had PSA > 0.5 ng/mL; and 29% had pN1 disease.

There was no statistically significant benefit for the experimental arm observed in the preplanned analyses of stratification subgroups defined as PSA < 0.5 ng/mL, pN0, or pN1.

Adverse events were consistent with the known safety profiles of each agent included in the study. “More rash, hypertension, slightly more diarrhea, and slightly more fatigue were observed in the experimental arm,” Dr. Nguyen said.

Disclosure: For full disclosures of the study authors, visit

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