The addition of abiraterone acetate and apalutamide to standard of care gonadotropin-releasing hormone (GnRH) agonist for 6 months and radiation therapy failed to improve progression-free survival and metastasis-free survival after prostatectomy compared to bicalutamide plus a GnRH agonist and radiation therapy in the phase III FORMULA-509 trial. The study population comprised patients with a detectable PSA (> 0.1 ng/mL) post radical prostatectomy and at least one high-risk feature. Of note, this 6-month intensified systemic therapy regimen did improve outcomes in the prespecified and stratified subgroup of patients with a PSA level higher than 0.5 ng/mL at baseline. Based on these findings, presented at the 2023 ASCO Genitourinary (GU) Cancers Symposium,1 this regimen may be considered a treatment option for postprostatectomy patients who meet that criterion.
In the overall trial, the 3-year progression-free survival rate was 74.9% for the experimental arm vs 68.5% for the group of patients who received 6 months of salvage radiation plus a GnRH agonist and bicalutamide (P = .06). The 3-year metastasis-free survival rate was 90.6% vs 87.2%, respectively (P = .05).
In a preplanned subgroup analysis of men with a baseline PSA level higher than 0.5 ng/mL, the 3-year progression-free survival rate was 67.2% vs 46%, respectively (P = .03). The 3-year metastasis-free survival rate was 84.3% vs 66.1%, respectively (P = .02). The number needed to treat to achieve this benefit was 5. Critically, randomization was stratified for the PSA criterion.
Paul L. Nguyen, MD
“There was no benefit [for intensification of therapy] in patients with a baseline PSA level up to 0.5 ng/mL,” stated lead author Paul L. Nguyen, MD, the Baldwin-Politi Distinguished Chair in Oncology and Professor of Radiation Oncology at Dana-Farber/Brigham and Harvard Medical School, Boston. “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 androgen-deprivation therapy may improve progression-free 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 a subgroup of 100 patients with a PSA level higher than 0.5 ng/mL at baseline. The absolute improvement in metastasis-free survival at 3 years was about 18% favoring the experimental arm.”
Dr. Nguyen continued: “The results are relevant for a patient who is getting salvage radiation for a rising PSA level after prostatectomy, and the PSA level is greater than 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 androgen-deprivation therapy to 24 months or, as the FORMULA-509 data suggest, keep the duration of 6 months of androgen-deprivation therapy and add abiraterone and apalutamide. This is an attractive option for patients for whom you need to intensity treatment beyond 6 months of regular androgen-deprivation therapy.” FORMULA-509 is the first formal study of this intensified regimen, he noted.
As Dr. Nguyen explained, 6 months of a GnRH agonist (androgen-deprivation therapy) plus salvage radiation therapy is the standard of care for men with prostate cancer and unfavorable features plus a detectable PSA level after 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 9 sites with unfavorable risk factors after prostatectomy. These factors included a PSA level of at least 0.1 ng/mL after radical prostatectomy and one or more of the following features: Gleason score 8–10; PSA level > 0.5 ng/mL; pT3/T4, pN1 or radiographic N1; PSA doubling time of up to 10 months; negative surgical margins; persistent PSA level; gross local or regional disease; or high Decipher prostate risk score.
All patients received salvage radiation therapy plus 6 months of a GnRH agonist. They 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 those with lymph node–negative disease (pN0).
At baseline, median patient age was 65 years; 35% had a Gleason score of 9; median PSA level was 0.3 mg/mL; 31% had a PSA level higher than 0.5 ng/mL; 29% had pN1 disease.
The primary endpoint was PSA progression–free survival, and the secondary endpoint was metastasis-free survival as assessed by conventional imaging. At study entry, stratification factors were a PSA level higher than 0.5 ng/mL vs lower than 0.5 ng/mL and pN0 vs PN1.
At a median follow-up of 34 months, the 3-year progression-free survival was 74.9% for the experimental arm vs 68.5% for the bicalutamide arm (P = .06). The 3-year metastasis-free survival rates were 90.6% for the experimental arm and 87.2% for the bicalutamide arm (P = .05).
The abiraterone plus apalutamide–containing arm was significantly superior in patients with a baseline PSA level higher than 0.5 ng/mL, according to a preplanned analysis by stratification (P = .03). The 3-year progression-free survival was 67.2% for the experimental arm vs 46.8% for the bicalutamide arm. The 3-year metastasis-free survival was 84.3% for the experimental arm vs 66.1% for the bicalutamide arm (P = .02). There was no statistically significant benefit for the experimental arm observed in the preplanned analyses of stratification subgroups defined as a PSA level less than 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.
At the conclusion of his presentation, Dr. Nguyen noted that the results in FORMULA-509 compared favorably with the results of the RADICALS-HD trial,2 which evaluated 24 months of androgen-deprivation therapy. “You can’t compare the two trials directly, but it appears that 6 months of androgen-deprivation therapy looks as good as 24 months in this study. This will be formally tested in the PROSTATE-IQ study,” he added.
Neha Vapiwala, MD, FACR, FASTRO, FASCO
Radiation oncologist Neha Vapiwala, MD, FACR, FASTRO, FASCO, Co-Chief of Genitourinary Oncology and Dean of Admissions at the University of Pennsylvania’s Perelman School of Medicine, commented on take-away points from the FORMULA-509 trial.
“As reported, this is a negative study that didn’t meet statistical significance for the primary or secondary endpoint, both of which are very relevant outcomes that matter to patients. However, the data suggest there is potential value with the addition of abiraterone and apalutamide to standard of care treatment [6 months of salvage radiation plus 6 months of GnRH therapy] in patients with PSA levels above 0.5 ng/mL after radical prostatectomy.”
Dr. Vapiwala continued, “This approach looked promising in the subgroup with higher PSA levels. The study results also suggest that 6 months of intensified systemic therapy may suffice in this subgroup, rather than standard androgen deprivation for 2 years, which in turn carries greater risk of prolonged side effects. The question will be what happens with additional follow-up. Recall that the purpose of this study was to evaluate how we can improve outcomes in the salvage setting, where we know there is still a significant percentage of patients for whom the current standard of care does not achieve disease control. Could hitting them harder with intensification of systemic therapy improve outcomes? For the overall group, at present the answer appears to be no.”
Turning to another issue, Dr. Vapiwala said she was surprised this approach did not pan out in those with N1 disease at this time, who are inherently at higher risk of disease progression and distant metastases, and thus should be more likely to benefit. Lack of pelvic nodal radiation in the majority of FORMULA-509 patients is also an issue, as including nodes is now generally considered standard in this population. Dr. Vapiwala is the principal investigator of the phase III INDICATE trial (ECOG/ACRIN 8191), which will evaluate a similar patient population (rising PSA level > 0.5 ng/mL after prostatectomy, or > 0.2 ng/mL if within 12 months after prostatectomy) with a double randomization to explore positron-emission tomography (PET)-directed treatment intensification with apalutamide and/or metastasis-directed radiation added to standard-of-care pelvic and prostate bed radiation and 6 months of androgen-deprivation therapy vs the standard of care alone.
“The eligibility criteria for INDICATE allow for any pathologic nodal status as well as PET-positive intrapelvic nodes, and all patients will receive pelvic nodal radiation,” she noted. “So this study should shed further light on the impact of systemic treatment intensification based on nodal status.”
DISCLOSURE: Dr. Nguyen owns stock in Volatilyx and Nanocan; served as a consultant or advisor to Astellas Pharma, Augmenix, Bayer, Blue East Diagnostics, Boston Scientific, Cota, Dendreon, Gerring, GenomeDx, Janssen, Myovant Sciences, and Nanobiotix; and received research funding from Astellas Pharma, Bayer, and Janssen. Dr. Vapiwala reported no conflicts of interest.
1. Nguyen PL, Kollmeier M, Rathkopf DE, et al: FORMULA-509: A multicenter randomized trial of post-operative salvage radiotherapy and 6 months of GnRH agonist with or without abiraterone acetate/prednisone and apalutamide post-radical prostatectomy. 2023 ASCO GU Cancers Symposium. Abstract 303. Presented February 16, 2023.
2. Parker CC, Clarke N, Cook A, et al: Duration of androgen deprivation therapy with post-operative radiotherapy for prostate cancer: First results of RADICALS-HD trial. ESMO Congress 2022. Abstract LBA9. Presented September 12, 2022.
Formal discussant of the FORMULA-509 trial, Tyler Seibert, MD, PhD, of the University of California San Diego, commented: “The important take-away of these results is who benefited from the intensification arm. The overall cohort with a PSA [prostate-specific antigen] level up to 0.5 ng/mL did not, ...