By Amar U. Kishan, MD, University of California, Los Angeles
Three large published randomized trials suggest a biochemical control benefit to adding hormonal therapy to salvage radiotherapy (SRT) for men with recurrent prostate cancer after radical prostatectomy. Of the two trials that utilized gonadotropin releasing hormone (GnRH)-agonist based hormonal therapy, one with longer follow-up (GETUG-16) showed a long-term improvement in PSA progression-free survival (PFS) and a retrospectively determined improvement in metastasis-free survival (MFS); the other trial (RTOG 0534) has only reported five-year results. A third trial, which used anti-androgen monotherapy (RTOG 9610), found an overall survival (OS) benefit with long-term follow-up; however, this benefit appears to be primarily restricted to patients with PSA levels ≥0.7 ng/mL at the time of SRT. In the intact prostate setting, one large randomized trial (STAMPEDE) has shown improvements in both MFS and OS in men receiving abiraterone acetate and prednisone (AAP) in addition to GnRH agonist therapy in the context of patients with particularly aggressive disease features. A natural question is whether hormonal therapy intensification in the SRT setting may similarly lead to important outcome improvements in men with higher-risk features.
The FORMULA-509 trial, led by Paul Nguyen, MD, FASTRO, was designed to answer this question. In this multi-center, open-label randomized trial, patients with aggressive features (PSA≥0.1 post-RP and one or more of Gleason 8-10, PSA>0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative margins, persistent PSA, gross local/regional disease, or Decipher High Risk) were randomized to receive SRT plus six months of GnRH agonist therapy plus bicalutamide 50 mg versus six months of GnRH agonist therapy plus AAP 1000 mg/5mg plus apalutamide (Apa) 240 mg daily. The primary endpoint was PSA-based PFS, with MFS as a secondary endpoint. The study had 80% power and one-sided type I error of 0.05 to detect a 50% improvement in PFS. Patients were stratified by PSA at study entry (>0.5 vs.≤0.5) and pathological nodal status. Analyses within these subgroups were pre-planned and utilized two-sided p-values.
From November 2017 to March 2020, 345 patients were randomized. With a median follow-up of 34 months, three-year PFS was 74.9% for AAP/apa vs. 68.5% for bicalutamide (hazard ratio [H] 0.71, 90% confidence interval [CI] 0.49-1.03, p=0.06). Three-year MFS was 90.6% with AAP/apa vs. 87.2% with bicalutamide (HR 0.57, 90% CI 0.33-1.01, p=0.05). Among the subgroup of patients with PSA >0.5, AAP/apa significantly improved PFS, with three-year rates of 67.2% vs. 46.8% (HR 0.50, 95% CI 0.27-0.95, p=0.03. Three-year MFS was also improved from 66.1% to 84.3% (HR 0.32, 95% CI 0.13-0.84, p=0.02 (2-sided). More rash and hypertension were seen in the AAP/apa arm.
Overall, the results of the FORMULA-509 trial suggest a meaningful benefit to hormonal therapy intensification in patients receiving SRT, particularly among those with PSA >0.5 at the time of SRT. An open question remains whether the dual intensification is necessary; in the aforementioned STAMPEDE trial, there was no advantage to adding enzalutamide and AAP together to GnRH agonists. Another question is how the use of prostate specific membrane antigen positron emission tomography might impact these findings, both due to extrapelvic and/or visible nodal disease at the time of SRT, and detection of extrapelvic disease during follow-up.
Abstract 259 - FORMULA-509: A Multicenter Randomized Trial of Post-Operative Salvage Radiotherapy (SRT) and 6 Months of GnRH Agonist with Either Bicalutamide or Abiraterone Acetate/Prednisone (AAP) and Apalutamide (Apa) Post-Radical Prostatectomy (RP) was presented on October 3, 2023 during the SS 28: GU 4: Radiotherapy for Kidney Cancer and Post-Prostectomy session at the 2023 ASTRO Annual Meeting.
