Hidden Metastases Revealed:

PSMA-PET imaging in prostate cancer patients with high-risk biochemical recurrence: implications from an “EMBARK-Like” cohort | Prostate Cancer and Prostatic Diseases

How PSMA-PET Scanning Is Rewriting the Rules for Men with Recurring Prostate Cancer

A new study — and a landmark trial — are forcing doctors to rethink who is really "non-metastatic"

Bottom Line Up Front (BLUF)

When prostate cancer returns after surgery or radiation and PSA is rising fast, doctors have traditionally called it "non-metastatic" if a standard CT scan and bone scan showed nothing. A major new study published in February 2026 shows that nearly half of those high-risk patients actually do have metastatic disease — the cancer has already spread — but only the newer PSMA-PET scan can find it. Separately, the landmark EMBARK trial has now demonstrated that intensifying treatment with a combination of enzalutamide (Xtandi) plus standard hormone therapy not only delays cancer spread but also extends overall survival by more than 40% versus hormone therapy alone. Together, these developments raise a critical and still-unanswered question: for the many men whose PSMA-PET reveals a handful of visible metastases, should those spots be targeted with precise radiation — in addition to systemic drug therapy — to achieve the best possible outcome? Clinical trials are actively working to answer that question right now.

Background: What Is Biochemical Recurrence, and Why Does It Matter?

After prostatectomy (surgical removal of the prostate) or radiation therapy, somewhere between 20% and 50% of men will experience what doctors call biochemical recurrence (BCR) — a return of measurable PSA in the blood, signaling the cancer has come back somewhere in the body. This can happen months or even years after initial treatment appears successful.

BCR by itself does not always mean the cancer will spread quickly, but certain warning signs indicate high risk. The most important of these is a PSA doubling time (PSADT) of 9 months or less — meaning PSA doubles every 9 months or faster. Men with this pattern are at substantially elevated risk of developing visible metastases and ultimately dying of prostate cancer.

For decades, doctors have used conventional imaging — a CT scan plus a bone scan — to determine whether cancer has spread at the time of BCR. If those scans were negative, patients were classified as having "non-metastatic" disease. That classification drove treatment decisions. But conventional imaging has well-known blind spots: it cannot reliably detect tiny deposits of cancer, particularly small lymph node metastases, and it often gives a falsely reassuring result.

The New Imaging Revolution: PSMA-PET Scans

PSMA stands for Prostate-Specific Membrane Antigen, a protein that prostate cancer cells display on their surface in large quantities. PSMA-PET scanning uses a radioactive tracer that seeks out and binds to PSMA-positive cancer cells throughout the body, then lights them up on a PET (positron emission tomography) scan. The result is a whole-body "molecular map" of where cancer is hiding — far more sensitive than conventional imaging, especially at the low PSA values typical of early recurrence.

Three PSMA-PET tracers are now FDA-approved in the United States:  

• ⁶⁸Ga-PSMA-11 (Illuccix),  
• ¹⁸F-DCFPyL (Pylarify), and  
• ¹⁸F-flotufolastat (Posluma). 

All three are increasingly available at major medical centers and are now recommended by the National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) as the preferred imaging tool when conventional scans are negative or inconclusive in men with BCR.

How much better is PSMA-PET? Meta-analyses report pooled sensitivities and specificities often above 90% for detecting metastases. Crucially, even at very low PSA levels (0.2–0.5 ng/mL after surgery), roughly half of men scanned will have positive PSMA-PET findings. And when PSA is rising quickly — as in high-risk BCR — detection rates climb even higher, approaching 80% or more in recent studies.

The New Study: "EMBARK-Like" Patients Scanned with PSMA-PET

The study that prompted this article was published on February 25, 2026, in the journal Prostate Cancer and Prostatic Diseases. The research team, led by Dr. Matteo Droghetti and colleagues from multiple European centers (including Bologna, Milan, Brussels, and São Paulo), set out to answer a pointed question: if you take patients who would have qualified for the landmark EMBARK trial and scan them with PSMA-PET instead of conventional imaging, how many of them are truly "non-metastatic" — and how many actually have spread disease?

The EMBARK trial was a large, Phase 3 randomized study that enrolled men with high-risk BCR (defined as PSADT of 9 months or less) who had no evidence of metastases on conventional CT and bone scans. EMBARK enrolled and treated these men as "non-metastatic." This is the standard clinical definition, and it is how the FDA approval for enzalutamide in this setting is worded. But what if conventional imaging missed significant disease in many of these patients?

To find out, the Droghetti team reviewed 587 patients with BCR after radical treatment who had undergone PSMA-PET scans. They identified 169 patients (29%) who met the same EMBARK eligibility criteria — high-risk BCR with no known metastases by conventional standards. These are exactly the patients currently being offered intensified hormonal therapy based on EMBARK results.

When they examined the PSMA-PET results for this "EMBARK-like" group, the findings were striking:

• 82% Had a positive PSMA-PET for any site of disease
• 46% Had metastatic disease visible on PSMA-PET
• 2.23 Median PSA (ng/mL) — nearly 5× higher than non-high-risk patients
• 4.3 mo Median PSA doubling time — far shorter than the 9-month comparison group

For comparison, among patients who did not meet EMBARK high-risk criteria, only 39% had any positive PSMA-PET finding and only 15% had metastatic disease. The difference was highly statistically significant (p < 0.001 for both comparisons).

In plain language: nearly half the men who would be classified as "non-metastatic" under current clinical standards are actually already living with visible metastatic disease, detectable only with PSMA-PET. They have been flying under the radar of standard imaging for years. This finding does not change the bottom line for treatment — these men clearly need and benefit from systemic therapy — but it profoundly changes the clinical picture and opens up an important additional question about whether those visible metastases should also be directly targeted.

The EMBARK Trial: A New Standard of Care — Now With Survival Data

The EMBARK trial (NCT02319837), funded by Pfizer and Astellas Pharma, enrolled 1,068 men with high-risk BCR between 2015 and 2019 at centers worldwide. Patients were assigned to one of three groups: enzalutamide (Xtandi, 160 mg daily) plus leuprolide (standard hormone therapy/ADT), enzalutamide alone (monotherapy), or leuprolide alone. None of the patients had detectable metastases on conventional imaging at enrollment.

Initial results published in the New England Journal of Medicine in October 2023 showed that enzalutamide plus leuprolide dramatically reduced the risk of developing metastases or dying by 58% compared to leuprolide alone (hazard ratio 0.42, p < 0.001). The five-year metastasis-free survival was 87.3% in the combination group versus 71.4% with leuprolide alone — a remarkable improvement. Enzalutamide monotherapy was also better than leuprolide alone (HR 0.63, p = 0.005), though the advantage was more modest.

Crucially, long-awaited overall survival data were presented at ESMO 2025 and published in the NEJM in October 2025: at a median follow-up of 8 years, the combination of enzalutamide plus leuprolide produced a greater than 40% reduction in deaths compared to leuprolide alone. This is a genuinely practice-changing result — it means that intensifying treatment at the time of high-risk BCR, before conventional imaging even shows metastases, extends life. Enzalutamide monotherapy, however, did not achieve a statistically significant overall survival benefit compared to leuprolide alone in the final analysis, making the combination the preferred standard.

Quality of life analysis from EMBARK, also published in late 2025, confirmed that both enzalutamide-containing regimens preserved health-related quality of life compared to leuprolide alone, with no clinically meaningful deterioration in overall FACT-P scores. Hormonal side effects such as sexual dysfunction were more common earlier with combination therapy, as expected with ADT, but did not translate into a meaningful difference in overall well-being.

The FDA and EMA have approved enzalutamide for this BCR indication. NCCN guidelines now include it as a recommended option for men with high-risk BCR.

What Does This Mean for You? If you have had surgery or radiation for prostate cancer and your PSA is now rising rapidly (doubling in 9 months or less), you should discuss both a PSMA-PET scan AND the possibility of intensified hormonal therapy with your oncologist. The EMBARK data show you may be able to significantly reduce your risk of metastatic spread and improve your chances of long-term survival by adding enzalutamide to standard ADT.

Combining the Two: What Should Be Done When PSMA-PET Finds Metastases?

This is the frontier of the field — and the most clinically urgent unanswered question raised by the new study. If a man with high-risk BCR has PSMA-PET imaging and it reveals, say, two lymph node metastases and a small bone lesion, what is the best strategy?

Option 1 is to treat systemically only — give enzalutamide plus ADT as EMBARK demonstrated, and rely on the drugs to control all disease throughout the body. This is supported by the EMBARK data and is clearly effective.

Option 2 is metastasis-directed therapy (MDT) — using precise, high-dose stereotactic body radiation therapy (SBRT, also called SABR) to ablate each visible metastasis identified on PSMA-PET, either alone or in combination with systemic drug therapy.

The rationale for MDT is compelling. Treating only with systemic therapy leaves known lesions in place. Eliminating visible disease with targeted radiation while simultaneously controlling microscopic (invisible) disease with drugs might produce better outcomes than either approach alone. And randomized trial data in oligometastatic prostate cancer (1–5 metastases) supports this concept:

The ORIOLE trial randomized 54 patients with recurrent oligometastatic prostate cancer detected on PSMA-PET to SBRT versus observation. Consolidation of all PSMA-positive disease with SBRT decreased the risk of new lesions at 6 months from 63% to 16% (p = 0.006). The STOMP trial and long-term data combining STOMP and ORIOLE confirmed durable benefits of MDT in this setting. A 2025 study using PSMA-PET-directed SBRT (35 Gy in 5 fractions) reported a 5-year local control rate of 86% for treated metastases in bone and lymph nodes — an impressive result.

The RADIOSA trial added ADT to SBRT for hormone-sensitive oligorecurrent disease, extending median clinical progression-free survival from 15.1 months with SBRT alone to 32.2 months with SBRT plus ADT (HR 0.43, p = 0.001). This suggests that combining local and systemic approaches is superior to either alone.

Perhaps most exciting is the groundbreaking LUNAR trial (NCT05496959), results of which were presented at ASTRO 2025. This Phase II study tested whether adding a PSMA-targeted radiopharmaceutical — specifically ¹⁷⁷Lu-PNT2002 — to SBRT for hormone-sensitive oligorecurrent prostate cancer (1–5 lesions on PSMA-PET) could address both the visible metastases (via SBRT) and invisible microscopic disease (via the systemic radiopharmaceutical). Ninety-two patients were enrolled. Local control with SBRT was excellent in both groups (98–100%). The radiopharmaceutical addition meaningfully delayed progression, with nearly all progression events (98%) being new metastases rather than regrowth at treated sites — underscoring that "invisible" disease remains a dominant driver of failure. While ¹⁷⁷Lu-PNT2002 remains investigational in this early-disease setting (it is currently approved only for later-stage metastatic castration-resistant prostate cancer), LUNAR is the first randomized trial to show that PSMA-targeted radioligand therapy can delay progression when added to metastasis-directed SBRT in earlier-stage recurrent disease.

Additional trials are now addressing exactly the combination the Droghetti paper highlights as critical. The PSMA-DC trial (NCT05939414) is comparing SBRT alone versus SBRT plus four cycles of ¹⁷⁷Lu-PSMA (7.4 GBq every 6 weeks) in men with 5 or fewer PSMA-positive lesions and at least one M1 site on PSMA-PET. The primary endpoint is conventional imaging-based metastasis-free survival. Other trials are evaluating whether adding ARPI drugs to SBRT (as in the SATURN trial) can further extend outcomes.

The bottom line from current evidence is that systemic therapy (enzalutamide plus ADT) must be the foundation — the EMBARK survival data make that clear. The open question is whether ablating PSMA-PET–visible lesions with SBRT provides additional benefit on top of an already-effective systemic regimen. Experts agree: the optimal combination strategy is a priority research question, and men with high-risk BCR and positive PSMA-PET should ideally be evaluated for clinical trial participation.

How PSMA-PET Changes Staging and the "Will Rogers Phenomenon"

Doctors and researchers are aware of an important statistical wrinkle that comes with any more sensitive diagnostic test. When a better test upstages patients — moving some from "non-metastatic" to "metastatic" — it can make both groups appear to do better simply by redistributing patients. This is called the "Will Rogers phenomenon" (named after the comedian who quipped that when Oklahomans moved to California, they raised the average intelligence of both states). With PSMA-PET detecting small-volume metastases previously invisible, some patients who would have been in the "non-metastatic" category are reclassified as "metastatic" but with very limited disease — making the non-metastatic group healthier (better outcomes) and the newly identified low-volume metastatic group also healthier (better outcomes) than the previous large metastatic group. This doesn't mean the new scan isn't beneficial, but it does mean clinical trial results that span the pre- and post-PSMA-PET era need careful interpretation. Researchers at leading centers are actively working on new trial frameworks (such as the PCWG4 guidelines and SPARC reporting standards) to account for this in future studies.

What You Should Ask Your Doctor

If you have biochemical recurrence after surgery or radiation, here are the key questions to bring to your next appointment:

"Is my PSA doubling time 9 months or less?" This is the primary criterion for high-risk BCR. If yes, you are in the group most likely to benefit from intensified treatment.

"Should I have a PSMA-PET scan?" Both NCCN and AUA guidelines now strongly support using PSMA-PET as the preferred imaging for BCR, particularly when conventional imaging is negative. Three FDA-approved tracers are available. If your center doesn't offer it, ask for a referral.

"Am I a candidate for enzalutamide plus ADT based on EMBARK?" If you have high-risk BCR and no prior metastases, the EMBARK overall survival data now support intensifying to enzalutamide plus ADT as a standard option.

"If my PSMA-PET shows limited metastases, can my spots be treated with SBRT?" This is a rapidly evolving area. Ask whether you qualify for metastasis-directed radiation to PSMA-PET–positive lesions, and whether doing so alongside systemic therapy might be appropriate — or whether a clinical trial is available.

"Are there clinical trials I should consider?" Studies like PSMA-DC and others are enrolling patients with exactly this profile. Clinical trial participation advances the science for everyone and may provide access to the next generation of treatment.

Quick Glossary

BCR (Biochemical Recurrence): Return of measurable PSA after surgery or radiation, indicating cancer has returned.

PSADT (PSA Doubling Time): How quickly PSA doubles. Shorter = more aggressive. ≤9 months is "high-risk."

PSMA-PET: An advanced scan that finds prostate cancer cells throughout the body using a radioactive tracer that targets the PSMA protein.

ADT (Androgen Deprivation Therapy): Hormone therapy that lowers testosterone, slowing prostate cancer growth. Also called "hormone therapy."

ARPI (Androgen Receptor Pathway Inhibitor): A class of drugs — including enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) — that block testosterone's effect on cancer cells, more powerfully than ADT alone.

Enzalutamide (Xtandi): An ARPI used in EMBARK, now FDA-approved for high-risk BCR when combined with ADT.

MDT / SBRT / SABR: Metastasis-Directed Therapy using Stereotactic Body Radiation Therapy — a highly precise, high-dose form of radiation that can ablate individual metastatic lesions with minimal side effects.

Oligometastatic disease: A limited number (typically 1–5) of metastases — considered an intermediate state where local treatments may still be curative or effective.

¹⁷⁷Lu-PSMA (Lutetium PSMA, Pluvicto): A radioligand therapy that delivers targeted radiation to PSMA-positive cancer cells throughout the body. Approved for later-stage disease; being tested earlier in trials like LUNAR.

Looking Ahead

The convergence of PSMA-PET imaging and intensified systemic therapy is fundamentally transforming how doctors approach high-risk BCR. What was once considered a vague warning signal — a rising PSA on otherwise negative scans — can now be mapped with molecular precision across the body. And what was once managed with standard ADT alone can now be treated with a survival-extending combination of ADT plus enzalutamide.

The next chapter is about combining the best of both worlds: using PSMA-PET to find every visible lesion, ablating those lesions with precision radiation, and simultaneously using systemic therapy to address what the camera still can't see. Clinical trials are writing that chapter now, and results should begin emerging over the next 2–4 years.

For men living with high-risk BCR today, the message is one of genuine hope — and of the importance of being informed, proactive, and connected to a specialist team that is keeping pace with rapid change in this field.

Verified Sources and Formal Citations

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