PAM50 Biomarker May Predict Apalutamide Efficacy in Prostate Cancer

The addition of apalutamide (Erleada) to secondary radiotherapy (SRT) produced clinically meaningful benefits among patients with recurrent prostate cancer and luminal B tumors, supporting PAM50 as a validated biomarker that may guide the use of hormone therapy, according to a presentation on findings from the phase 2 NRG GU006 (BALANCE) trial (NCT03371719) presented at the 2025 American Society for Radiation Oncology (ASTRO) Annual Meeting.¹

At 5 years, the biochemical progression-free survival (PFS) rate was 72% in the apalutamide arm vs 54% in the placebo arm among those with luminal B disease (HR, 0.45; 95% CI, 0.24-0.86; P = .0062). Among those with non-Luminal B disease, the 5-year biochemical PFS rates were 70% vs 71% in each respective arm (HR, 0.95; 95% CI, 0.65-1.41; P = .44).

The 5-year metastasis-free survival (MFS) rates in the luminal B subgroup were 95% with apalutamide vs 82% with placebo (HR, 0.27; 95% CI, 0.07-0.95; P = .029). Additionally, the 5-year MFS rates were 90% and 89% in each respective arm among those with non-luminal B status (HR, 1.06; 95% CI, 0.41-2.78; P = .90).

“We’ve been searching for decades for a way to determine which patients are most likely to respond to hormone therapy after prostatectomy. We now have a tool that lets us tailor treatment based on a tumor’s biology and recommend hormone therapy only for those patients who we think can expect to see a benefit,” lead study author Daniel Spratt, MD, professor and chair of radiation oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University School of Medicine, stated in a press release on these findings.² “This is the first prospectively validated predictive biomarker in prostate cancer. It gives us a promising way to personalize care, recommending hormone therapy for those who respond, and avoiding unnecessary treatment when it is unlikely to help.”

Spratt and co-authors noted that recurrence following radical prostatectomy may occur in 40% to 80% of patients with intermediate- and high-risk prostate cancer across clinical trials. Consequently, SRT serves as a generally preferable option vs adjuvant radiotherapy for most patients.

The study investigators also highlighted a lack of prospectively validated predictive biomarkers for the efficacy of hormone therapy in this population, as hormone therapy in unselected patients receiving early SRT typically does not confer improved overall survival. Furthermore, Spratt and colleagues developed a novel luminal-based classification adapted from the breast cancer PAM50 signature in 2015. These investigators aimed to test the hypothesis that those with transcriptionally defined luminal B tumors would experience greater efficacy with apalutamide while undergoing SRT for recurrent prostate cancer after radical prostatectomy.

Investigators collected PAM50 subtype data on 295 patients with a prostate antigen (PSA) level of 0.1 to 1.0 ng/mL and recurrent disease following radical prostatectomy. Additionally, patients were stratified based on positive or negative surgical margins, pre-SRT PSA levels of less than 0.5 ng/mL or 0.5 to 1.0 ng/ML, and luminal B (n = 127) or non-luminal B subtype (n = 168). Investigators then randomly assigned patients 1:1 to receive SRT at 64.8 to 70.2 Gy in 33 to 39 fractions plus 6 mg of apalutamide or matched placebo.

The trial’s primary end point was biochemical PFS. Secondary end points included MFS, distant metastasis, salvage hormone therapy use, and toxicity.

Grade 3 or higher adverse effects (AEs) of any attribution occurred in 32% of the apalutamide arm and 23% of the placebo arm. In each respective arm, grade 3 or higher toxicities included hypertension (13% vs 5%), rash (5% vs 0%), cardiac disorders (0.7% vs 1.3%), and falls (0.7% vs 1.3%). Across the overall cohort, other notable toxicities included hematuria (1%), diarrhea (1%), non-infective cystitis (0.3%), and rectal bleeding (0.3%).

“The magnitude of benefit—and the complete lack of benefit in some patients—makes it unlikely that we could ethically enroll patients in a follow-up trial. PAM50 could now be used in recurrent prostate cancer to support shared decision making,” Spratt concluded.

References

1. Spratt DE, Karrison TG, Sandler HM. A double-blinded placebo-controlled biomarker stratified randomized trial of apalutamide (APA) and radiotherapy for recurrent prostate cancer (NRG GU006, BALANCE trial). Presented at the 2025 American Society for Radiation Oncology (ASTRO) Annual Meeting; September 27 – October 1, 2025; San Francisco, CA. Abstract LBA04.
2. First-of-its-kind genomic test predicts benefit from hormone therapy added to radiation for recurrent prostate cancer. News release. American Society for Radiation Oncology. September 28, 2025. Accessed September 29, 2025. https://tinyurl.com/2rcve4kk