A Potential Game-Changer in Prostate Cancer: A Simple Genomic Test Can Tell Us Who Needs Hormone Therapy And Who Doesn’t

For years, doctors have wrestled with a critical dilemma: when prostate cancer recurs after surgery, standard practice often involves adding hormone therapy (HT) to radiation treatment. While HT can be a powerful tool in blocking testosterone, it also comes with significant, life-altering side effects like fatigue, bone loss, and cardiovascular risk.

For decades, cancer experts have wrestled with the question, How do we know which patients truly need this difficult treatment and which patients can safely skip it?

The answer has finally arrived. At this year’s American Society for Radiation Oncology (ASTRO) 2025 Annual Meeting, researchers have validated a genomic test that reads the biology of the tumor itself to provide a definitive answer. This test is called PAM50.

Understanding the Recurrence Challenge

Patients dealing with a rising PSA after a radical prostatectomy can feel like a setback, but it is unfortunately common. For up to 30% of patients, the cancer will recur or persist, often indicated by an elevated PSA level.

When this happens, the standard next step is usually a course of salvage radiotherapy (SRT). Radiation therapy is an integral part of healing and can lead to cures in many cases. For patients whose PSA is rising after surgery, radiation therapy has been shown to improve survival.

The Role of Hormone Therapy

Until now, without a reliable predictive tool, the decision to add hormone therapy was often based on factors that were not specific enough to the tumor’s actual biology.

The Heavy Burden of Side Effects

While hormone therapy can be a lifesaver, we must acknowledge the difficulty of living with its side effects on patients. This treatment affects the entire body because it temporarily blocks a hormone that is essential for overall health. Dr. Daniel Spratt, the principal investigator of the BALANCE trial, noted that testosterone plays a crucial role in maintaining bone, muscle, cognitive, and cardiac health.

For patients who don’t actually need hormone therapy, subjecting them to these side effects is a heavy burden without a corresponding clinical reward.

The wide range of potential side effects associated with hormone therapy includes:

• Fatigue: A deep, persistent exhaustion that is often hard to manage.
• Hot Flashes: Sudden feelings of intense heat.
• Bone Loss: Increased risk of osteoporosis and fractures.
• Metabolic Changes: Weight gain or changes in metabolism.
• Cardiovascular Risk: Potential impact on heart health.

Putting patients through six months of treatment, leaving them with grueling side effects, only to learn in the end that there was no real benefit, is the fundamental problem doctors have been working for decades to solve. We needed a way to ensure that patients enduring this difficult treatment were the ones who would truly benefit from it.

The Scientific Breakthrough: Introducing PAM50

The scientific community has successfully developed a tool that finally provides that certainty. This tool is a gene expression test called PAM50.

PAM50 is a genomic test, meaning it looks deep inside the tumor cells and reads their genes. These genes tell us exactly how the tumor is behaving and what kind of fuel (or lack of fuel) it responds to. It’s like checking the engine specifications of a car to determine if it runs better on premium gas or regular gas.

A Lesson Learned from Breast Cancer

PAM50 was originally developed and successfully used to guide treatment for breast cancer. Just as breast tumors are classified based on receptor status (like estrogen receptor status, which guides endocrine therapy decisions), prostate tumors can also be grouped into distinct molecular subtypes. This genomic test captures that crucial prostate cancer biology.

By adapting and validating this test for prostate cancer, researchers can now identify exactly which molecular subtype of recurrent prostate cancer a patient has.

Unlocking the Subtypes: Luminal B vs. Non-Luminal B

The PAM50 test classifies recurrent prostate tumors into two main subtypes, which have vastly different needs when it comes to hormone therapy: Luminal B and Non-Luminal B. This classification is the heart of the breakthrough.

Subtype 1: Luminal B Tumors

• What they are: These tumors are transcriptionally defined, meaning they show a specific pattern of gene activity. Dr. Spratt and his colleagues discovered that Luminal B tumors grow more quickly and are highly dependent on testosterone.
• The Prediction: Because they rely so heavily on that hormone “fuel,” patients with Luminal B tumors are predicted to be the ones who will see the greatest benefit from hormone therapy. For these patients, blocking testosterone is incredibly effective.

Subtype 2: Non-Luminal B Tumors

• What they are: This group includes other subtypes, such as Luminal A and Basal-like tumors. Importantly, these tumors are generally less dependent on testosterone. They might be fueled by other mechanisms that hormone therapy cannot block.
• The Prediction: Patients with Non-Luminal B tumors are predicted not to respond well to hormone-based treatment added to their radiation.

This distinction is monumental. It moves us away from a one-size-fits-all approach and allows us to target only the tumors that are susceptible to hormone blockade.

The Definitive Proof: The BALANCE Trial (NRG GU006)

The promise of personalized medicine requires rigorous testing. The PAM50 test was validated in a crucial clinical trial known as the Phase II BALANCE trial (NRG Oncology GU006). This was not a small observation study; it was a prospectively validated, randomized trial. This level of rigorous testing is what gives us, as physicians, the confidence to change treatment standards.

How the Trial Worked

The BALANCE trial enrolled 295 patients across the U.S. who had recurrent prostate cancer after having a prostatectomy. All patients had rising PSA levels (86% had a PSA below 0.5 ng/mL at the start) and showed no signs that the cancer had spread to distant areas.

The median follow-up for these patients was a substantial five years.

Measuring Success: What We Tracked

The primary goal of the trial was to measure biochemical progression-free survival (bPFS), a key measure of whether the cancer has returned, based on PSA levels, local recurrence, distant metastasis, or death.

A key secondary measure was metastasis-free survival (MFS), which tracks the time patients remain free from the distant spread of the disease.

The Stunning Results: Customizing Care

The results of the BALANCE trial were so clear and definitive that they instantly validated the PAM50 test as a critical tool.

For the patients whose tumors were classified as Luminal B (representing about 43% of the study participants), the addition of hormone therapy (apalutamide) made a massive difference. These patients received significant improvement in clinically meaningful outcomes.

When we look at the five-year survival rates, the difference is profound:

• Biochemical Progression-Free Survival (bPFS):
  • Luminal B with Hormone Therapy (APA): 72.4%
  • Luminal B with Placebo: 53.9%

The benefit here is crystal clear: hormone therapy dramatically reduced the risk of the cancer coming back for this specific group.

• Metastasis-Free Survival (MFS):
  • Luminal B with Hormone Therapy (APA): 94.7%
  • Luminal B with Placebo: 81.8%

Nearly 95% of the Luminal B patients who received hormone therapy were free of metastasis five years later, compared to about 82% of those who received a placebo. This shows that hormone therapy is not just delaying recurrence but is actively lowering the risk of life-threatening metastatic disease.

The Power of Knowledge: Personalizing Care

This research, presented at the American Society for Radiation Oncology (ASTRO) Annual Meeting, represents an enormous leap forward. This is the first prospectively validated predictive biomarker in prostate cancer. What PAM50 gives you is the power of knowledge, which translates directly into personalized care.

Guiding Your Treatment Decision

Before this test, deciding whether to endure the side effects of hormone therapy was often a gamble, based on general statistics. Now, we have a way to recommend treatment explicitly tailored to your patient’s biology.
If you are discussing possible radiation treatment with a patient facing recurrent prostate cancer after surgery, here are some things to consider.

• If the PAM50 test shows the patient has a Luminal B tumor, the data strongly support adding six months of hormone therapy (like apalutamide) to your patient’s radiation. The clinical benefit is worth managing the temporary side effects.
• If the PAM50 test shows the patient has a Non-Luminal B tumor, the data show that adding hormone therapy will expose the patient to difficult side effects without improving their outcomes.

The fact that the results were so conclusive means that a follow-up trial is deemed unethical, as it would require giving a placebo to Luminal B patients who clearly benefit, or giving unnecessary hormone therapy to Non-Luminal B patients who don’t. This means the findings are so robust that they are considered practice-changing immediately.

This is a promise kept: we now have a promising way to personalize care, recommend hormone therapy for those who respond, and avoid unnecessary treatment when it is unlikely to help.