Use of PAM50 subtyping allowed clinicians to determine which patients with recurrent prostate cancer were most likely to benefit from the addition of apalutamide hormonal therapy to salvage radiotherapy, according to findings from the phase II BALANCE trial (NRG GU006). These results were presented during a press briefing at the 2025 American Society for Radiation Oncology (ASTRO) Annual Meeting.1
“PAM50 now represents the first and only prospectively validated predictive biomarker to guide hormone therapy across all of prostate cancer,” said principal investigator Daniel E. Spratt, MD, Professor and Chair of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University School of Medicine. “Patients with luminal B tumors derive clinically meaningful benefits, including metastasis-free survival, to the addition of apalutamide to secondary radiotherapy, and these benefits were not observed in non–luminal B patients.”
Background and Study Rationale
A majority of men with intermediate- to high-risk localized prostate cancer who undergo radical prostatectomy still experience recurrence after surgery. For recurrence, men are typically treated with salvage/early secondary radiotherapy and/or hormonal therapy. Although hormonal therapy may enhance the effects of radiation therapy and delay disease progression,2,3 it has been associated with significant declines in quality of life as well as risks for cardiovascular toxicities and metabolic changes.
PAM50 now represents the first and only prospectively validated predictive biomarker to guide hormone therapy across all of prostate cancer.— DANIEL E. SPRATT, MD
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No prospectively validated predictive biomarkers have previously existed to help guide the use of hormonal therapy.
Dr. Spratt and colleagues had adapted a luminal-basal classification tool based on the PAM50 signature, which was first created for use in breast cancer. The PAM50 classifier was previously used to subtype prostate cancer subtypes based on a luminal A or B or basal lineage.4 In the retrospective study, patients with basal or luminal A tumors derived a similar benefit—whether or not they received androgen-deprivation therapy—whereas patients with the luminal B subtype who received androgen-deprivation therapy experienced a significant survival benefit compared with those who did not receive hormonal therapy.
Luminal B tumors have been associated with the poorest clinical outcomes, and these patients typically have higher prostate-specific antigen (PSA) levels, Gleason scores, and rates of extracapsular extension and lymph node invasion.
For the BALANCE trial, the investigators assessed whether patients with luminal B tumors would derive greater benefit from apalutamide, a potent oral inhibitor of the androgen receptor, than those with non–luminal B tumors among men with recurrent prostate cancer receiving secondary radiotherapy after radical prostatectomy.
Study Methods
Men with prostate cancer who had undergone radical prostatectomy and had a PSA level between 0.1 and 1.0 ng/mL without nodal or distant metastasis were eligible for enrollment in the study. A total of 295 patients were enrolled and randomly assigned to receive secondary radiotherapy with placebo or apalutamide at 240 mg daily for 6 months. Radiotherapy consisted of external-beam radiation therapy of 64.8 to 70.2 Gy in 33 to 39 fractions. Participants were stratified by molecular subtype by PAM50 subtyping as luminal B or non–luminal B as well as by surgical margins and PSA levels prior to radiotherapy.
The primary endpoint was biochemical progression-free survival; or the first occurrence of biochemical, local, regional, or distant recurrence; or death. Secondary endpoints included metastasis-free survival, distant metastasis, and adverse events. Patients were followed for a median of 5 years.
Patient Characteristics and Study Findings
Of the participants, the median age was 65, 50% achieved positive surgical margins, 51% had pathologic T3 disease, 86% had initial PSA levels below 0.5 ng/mL, and 43% had a luminal B subtype.
In the group of patients with luminal B tumors, the 5-year biochemical progression-free survival rate was 72% for patients who received apalutamide vs 54% for patients who received placebo (hazard ratio [HR] = 0.45; 95% confidence interval [CI] = 0.24–0.86; P = .0062). “These [patients] are the ones we predicted would benefit more from hormone therapy, and that’s exactly what it showed,” Dr. Spratt explained.
On the other hand, patients with non–luminal B tumors had a 5-year biochemical progression-free survival rate of 70% in the apalutamide arm vs 71% in the placebo arm (HR = 0.95; 80% CI = 0.65–1.41; P = .44). “Very importantly, this trial was trying to see [if we can] identify who does not benefit, and in the non–luminal B patients, there is no benefit from apalutamide. At 5 years, they both have nearly identical estimates at about 70%,” Dr. Spratt said.
Similarly, metastasis-free survival was significantly improved in patients with luminal B tumors who received apalutamide compared with those who received placebo, with 5-year rates of 95% vs 82%, respectively (HR = 0.27; 95% CI = 0.07–0.95; P = .029). The 5-year metastasis-free survival rates in patients with non–luminal B tumors were similar at 90% with apalutamide and 89% without (HR = 1.06; 95% CI = 0.41–2.78; P = .90).
Safety
Grade 3 or higher adverse events were reported in 32% of patients given apalutamide vs 23% of patients in the placebo arm. In the apalutamide arm, rash was observed in 5% of patients; hypertension, in 13%; cardiac disorders, in 0.7%; and falls, in 0.7%. Radiation therapy was reported to be well tolerated, with hematuria and diarrhea each reported in 1% of patients in the overall cohort.
DISCLOSURE: The study was supported with funding from the National Institutes of Health, Janssen/Johnson & Johnson, and Veracyte. Dr. Spratt has received advisory board financial compensation from AstraZeneca, Astellas, Bayer, Boston Scientific, Blue Earth, GSK, Janssen, Novartis, and Pfizer.
REFERENCES
1. Spratt DE, Karrison TG, Sandler HM, et al: A double-blinded placebo-controlled biomarker stratified randomized trial of apalutamide and radiotherapy for recurrent prostate cancer (NRG GU006, BALANCE trial). 2025 ASTRO Annual Meeting. Abstract LBA 04. Presented September 29, 2025.
2. Carrie C, Magné N, Burban-Provost P, et al: Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16). Lancet Oncol 20:1740-1749, 2019.
3. Parker CC, Kynaston H, Cook AD, et al: Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer. Lancet 403:2416-2425, 2024.
4. Zhao SG, Chang SL, Erho N, et al: Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy. JAMA Oncol 3:1663-1672, 2017.
EXPERT POINT OF VIEW
Discussant of the BALANCE trial (NRG GU006), Chad Tang, MD, Associate Professor of Radiation Oncology, Translational Molecular Pathology, and Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, commented on the overall design of the trial and its results as well as next steps for this research:
“NRG GU006 is a well-designed phase II study where a selected form of therapy escalation is given in a biologically defined subset of patients with biochemically recurrent prostate cancer after prostatectomy. The study had a well-thought-out biological hypothesis, and its double-blind nature with placebo use for apalutamide speaks to its rigor. Dr. Spratt and his team deserve the highest praise for conducting this well-done trial in record time; that enrollment rate was incredible.”
Chad Tang, MD
Dr. Tang continued: “The interesting thing about this analysis, in my opinion, was how well the data spoke for the hypothesis. You couldn’t have asked for a better separation of curves and closure of the curves in the PAM50 luminal B vs non–luminal B subtypes. It’s not often that prospective data confirm biologic data to this extent, but in this case, it has in a big way.”
For Dr. Tang, the winner of this trial are the patients. “As all of my patients [would] tell you..., no man likes hormone therapy. So, the ability to help reduce that in a substantial subset of patients based on this biologic marker is a win for our patients,” he noted.
What Next?
According to Dr. Tang, the next step is a phase III trial. “But given these results,” he said, “it’s going to be a little hard to do that study. At a minimum, you should be able to monitor the effective PAM50 in postmarketing surveillance and look at larger data sets. From a 1,000-foot view of the field, there are a lot of biomarkers escalating and de-escalating for the subtype. So, what we are going to look for in the next 5 to 10 years is a comprehensive strategy that incorporates PAM50, Decipher, Artera, and I’m sure many other markers that come out, in a comprehensive algorithm to decide how our patients are escalating or de-escalating....”
DISCLOSURE: Dr. Tang has served as a consultant or advisor with Boston Scientific, Elekta, MOLLI Surgical, and Telix Pharmaceuticals; has received research funding from Noxopharm and Myriad Genetics; has a patent on the utilization of a monoclonal antibody which is licensed for use and receives royalties per year on this license; has received travel expenses from Vision RT; and has received royalties from Osler Institute for record materials.
