<p>A biomarker has yet to be identified for predicting which patients with recurrent prostate cancer will derive the most benefit from the addition of hormone therapy (HT) to secondary radiotherapy (RT). A study presented by Daniel E. Spratt, MD, at the recent <strong>2025 ASTRO Annual Meeting</strong> investigated the use of PAM50 molecular subtypes as a predictor of HT response in patients with a biochemical recurrence of prostate cancer.</p> <p><br></p> <p><em>Following his presentation, featured expert Daniel E. Spratt, MD, was interviewed by</em> Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Spratt on these findings are presented here.</em></p>

Secondary RT, formerly called salvage RT, is often used for patients who experience a biochemical relapse after undergoing a prostatectomy. In trials comparing the use of adjuvant RT with early secondary RT in those experiencing a biochemical relapse, there were no major differences in long-term outcomes. Based on this, the general recommendation is to wait until prostate-specific antigen (PSA) levels become detectable (≥0.1 ng/mL to 0.2 ng/mL) before providing early secondary RT.

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Several randomized trials have investigated the addition of HT to secondary RT in patients with recurrent prostate cancer. These trials showed that giving HT delays subsequent PSA recurrence, which makes sense because HT innately lowers PSA levels. However, most of these trials did not show significant improvements in metastasis-free survival, and no study has shown an improvement in overall survival (OS) in patients receiving HT and early secondary RT. We recently published a collaborative study–level meta-analysis of studies showing a hazard ratio of nearly 1 for OS when adding HT to early secondary RT. There were signals of a benefit to adding HT, but it is not a “slam dunk,” especially when looking at OS.

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Approximately a decade ago, a group that included Felix Y. Feng, MD, Shuang G. Zhao, MD, and me adapted the breast cancer PAM50 signature to prostate cancer. While breast cancer has 5 subtypes, we used 3 of these groups to represent prostate cancer: luminal A, luminal B, and basal. Based on a retrospective analysis, we determined that patients with luminal B tumor types derived the greatest benefit from postoperative HT. To test this, we conducted the first-ever prospective, biomarker-driven, randomized trial to determine whether PAM50 can predict treatment benefit with HT (ie, apalutamide) in addition to secondary RT.

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I presented results from this double-blind placebo-controlled trial at ASTRO 2025 (abstract LBA 04). In this trial, patients with intermediate- to high-risk prostate cancer were stratified by PAM50 molecular subtype (ie, luminal B subtype vs non–luminal B subtypes) and received 6 months of either placebo or apalutamide. Our primary end point was biochemical progression-free survival (bPFS), defined as the first occurrence of biochemical, local, regional, or distant recurrence, or death from any cause. After a median follow-up of 5 years, apalutamide significantly improved bPFS in patients with the luminal B subtype, while no such improvement was observed in patients with the non–luminal B subtypes, and the 5-year estimated bPFS was 72.4% vs 53.9% in the apalutamide vs placebo arms, respectively. Patients with the luminal B subtype receiving apalutamide plus secondary RT also experienced improvements in metastasis-free survival, while patients with the non–luminal B subtypes did not. Overall, these data show that PAM50 subtypes can help identify which patients are likely to benefit from short-term HT.

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I foresee the use of the PAM50 biomarker being incorporated into routine practice to personalize the treatment of prostate cancer. And, while it is important that we provide HT only to those patients who will benefit, we also do not want to assume that these results would be valid across all types of prostate cancer. Additional prospective studies are needed. I would caution providers not to use this type of information outside of the context in which it has been validated.

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Another therapy that has been investigated in this context is pelvic lymph node RT (PLNRT). At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, Alan Pollack, MD, PhD, presented additional data from the RTOG-0534 (SPPORT) clinical trial based on the Decipher risk score (Veracyte, Inc). The SPPORT trial investigated the addition of ADT and PLNRT with secondary RT in biochemically recurrent prostate cancer. The addition of PLNRT in unselected patients provides a small improvement in biochemical control at the expense of a mild increase in toxicity. Patients with a high Decipher score appear to derive greater benefits from PLNRT and may help personalize the use of this treatment.