When Scans Tell a Different Story:
Radiographic Progression and PSA in Advanced Prostate Cancer
Advanced Prostate Cancer Radiographic Progression and PSA Increase in Patients Treated With Enzalutamide - The ASCO Post
A patient-friendly summary of new research on disease monitoring with enzalutamide
Bottom Line Up Front
New research shows that in men with advanced prostate cancer taking enzalutamide, cancer can progress visibly on imaging scans (CT, bone scans, or MRI) without a corresponding rise in PSA levels. This happens significantly more often than previously recognized. The key takeaway: don't rely on PSA alone to monitor treatment response. Regular imaging studies are essential, even when PSA appears stable or is declining.
Understanding the Finding: A Tale of Two Measurements
For decades, prostate-specific antigen (PSA) has been the cornerstone of how doctors track whether advanced prostate cancer is responding to treatment. A falling PSA is reassuring; a rising PSA signals alarm. But a major new analysis published in the Journal of Clinical Oncology reveals a troubling disconnect: in a meaningful proportion of men treated with enzalutamide, cancer can be visibly progressing on imaging while the PSA blood test remains stable or continues to fall.
The research, led by Dr. Andrew Armstrong of Duke University, examined data from more than 2,500 patients across two landmark trials: ARCHES (men with metastatic hormone-sensitive prostate cancer) and PROSPER (men with nonmetastatic castration-resistant disease). The findings paint a sobering picture of what doctors call "discordance"—when the story told by imaging scans diverges from the story told by PSA.
By the Numbers: What the Research Found
In ARCHES (hormone-sensitive disease): Among men on enzalutamide plus hormone therapy who developed radiographic progression, one in four (25.3%) showed no rise in PSA whatsoever. More strikingly, six in ten (62.0%) did not meet standard PSA progression criteria. By comparison, in the control group receiving hormone therapy alone, this happened in only 7.4% and 38.3%, respectively.
In PROSPER (castration-resistant disease): The pattern was remarkably similar. Among men on enzalutamide who showed radiographic progression, 21.9% had no PSA rise, and more than half (51.3%) did not meet standard PSA progression definitions. In the control group, this occurred in only 3.6% and 18.8%, respectively.
The bottom line: Enzalutamide-treated patients were three to six times more likely to develop imaging-detected progression without corresponding PSA changes compared to those on conventional hormone therapy alone.
Why Does This Happen?
The mechanism is rooted in how enzalutamide works. This drug is an androgen receptor inhibitor—it blocks the hormone signals that fuel prostate cancer growth. When it works, it does so powerfully: PSA drops because the drug kills tumor cells and suppresses hormone-driven growth so effectively that the usual biochemical markers of disease activity become unreliable.
"After treatment with enzalutamide, PSA levels decline due to potent androgen receptor blockade and cell death," Dr. Armstrong and colleagues noted. "Although PSA decline is prognostic and associated with improved long-term outcomes, detection of radiographic progression could be delayed if imaging studies are only guided by PSA levels."
In other words: the very thing that makes enzalutamide a powerful drug—its ability to suppress PSA through aggressive androgen blockade—can mask the emergence of resistant tumor cells that show up on scans but don't immediately spike PSA. This is especially concerning with liver metastases, which appeared more than five times more frequently in enzalutamide-treated patients who developed radiographic progression.
The Prognostic Reality: What It Means for Survival
Here's what makes this finding clinically critical: radiographic progression is associated with worse overall survival, regardless of whether PSA has risen.
In ARCHES, patients who developed radiographic progression—whether or not they had PSA progression—had significantly shorter overall survival compared to those with no imaging progression. The same held true in PROSPER: radiographic progression, with or without PSA changes, predicted worse outcomes for men on enzalutamide.
This means detection of progression on imaging is not a false alarm or an incidental finding. It reflects real, meaningful disease progression that affects longevity and treatment options. Delaying detection because we were waiting for PSA to rise could cost patients valuable time.
Clinical Implications: What Does This Mean for You?
For patients on enzalutamide or similar drugs (abiraterone, darolutamide, apalutamide): Periodic imaging surveillance is now strongly recommended by the researchers, not optional or guideline-dependent. This likely means:
- Scheduled CT scans of the abdomen and pelvis at regular intervals (typically every 3–4 months, depending on your case)
- Bone scans or NaF-PET imaging if you have bone metastases
- Potentially PSMA-PET/CT imaging, which is increasingly available and may be more sensitive for detecting early progression than conventional CT or bone scans
For all advanced prostate cancer patients: Understand that PSA is one piece of a larger puzzle. A stable or falling PSA is reassuring, but it is not a complete picture. Clinical symptoms, imaging findings, and overall assessment must be considered together. If your doctor recommends imaging despite a "good" PSA number, this is not paranoia—it reflects current best evidence.
Questions to ask your oncologist:
- How frequently should I have imaging studies while on my current therapy?
- Are we using conventional CT/bone scan, or do I have access to PSMA-PET/CT?
- If my imaging shows progression but my PSA hasn't risen, what does that mean for my treatment plan?
- What imaging modalities are most appropriate for my disease pattern (bone-dominant vs. soft-tissue dominant)?
Context: Where This Fits in Current Practice
The Armstrong study adds empirical weight to what some experts had begun to suspect. In December 2025, the European Association of Urology published updated guidelines acknowledging that periodic imaging is advisable in advanced prostate cancer, particularly for patients receiving androgen receptor pathway inhibitors. The European consensus panel had previously warned that imaging discordance with PSA occurs, and that imaging should not be deferred based on PSA response alone.
Additionally, a 2025 systematic review found that among men with advanced castration-resistant disease, PSA and PSMA-PET imaging responses were discordant in approximately one-quarter of cases. This underscores that the Armstrong findings are not an anomaly but rather a recognized phenomenon that deserves clinical attention.
More sophisticated imaging modalities, particularly PSMA-PET/CT and whole-body MRI, are increasingly recognized as superior to conventional CT or bone scanning for detecting early progression and identifying sites of disease that produce minimal PSA.
A Patient Perspective
If you've been on enzalutamide or a similar drug and have been reassured by a falling PSA, this research is a reminder to stay engaged with imaging surveillance. The science tells us that "biochemical progression" (PSA rise) and "radiographic progression" (visible growth on scans) are not always synchronized. Your disease progression may be outpacing what your PSA tells you.
Conversely, this finding reinforces something many of us already sense: advanced prostate cancer is heterogeneous and unpredictable. A single biomarker—even one as widely used as PSA—cannot capture the full complexity of disease behavior. Our best defense is multimodal monitoring: PSA, imaging, clinical assessment, and ongoing dialogue with an oncologist who understands these nuances.
The Bottom Line
This landmark analysis from more than 2,500 patients across two major trials sends a clear message: when you're on enzalutamide or related drugs, imaging studies are not optional add-ons—they're essential. A stable PSA does not mean disease is stable. Pushing for regular scans isn't excessive caution; it's alignment with current evidence.
For patients managing advanced prostate cancer, knowledge is power. Understanding that imaging and PSA can diverge, and that detection of imaging progression carries real prognostic weight even without PSA rise, empowers you to advocate for appropriate monitoring and to interpret your own results more fully. Work closely with your oncology team to establish a monitoring strategy that captures the full picture of your disease, not just the PSA number.
Verified Sources and References
Primary Study
Armstrong AJ, Azad AA, Iguchi T, et al. Radiographic Progression With and Without Prostate-Specific Antigen Rise in Patients With Advanced Prostate Cancer Treated With Enzalutamide. Journal of Clinical Oncology. 2026 Mar 27. DOI: 10.1200/JCO-24-02829.
ASCO Post Summary
Stenger M. Advanced Prostate Cancer: Radiographic Progression and PSA Increase in Patients Treated With Enzalutamide. The ASCO Post. April 10, 2026.
Clinical News Coverage
Scans Uncover Hidden Prostate Cancer Progression When PSA Stays Stable. Northwestern University Feinberg School of Medicine News Center. April 24, 2026.
ARCHES Trial (Original Publication)
Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. Journal of Clinical Oncology. 2019 Nov 10;37(32):3038-3046.
PROSPER Trial (Original Publication)
Hussain M, Fizazi K, Saad F, et al. PROSPER Trial: Enzalutamide Improves Radiographic Progression-Free Survival and Overall Survival in Men With Nonmetastatic Castration-Resistant Prostate Cancer. Journal of Clinical Oncology. 2020 Jan 10;38(2):127-137.
PSA-Imaging Discordance (PREVAIL Analysis)
Petrylak DP, Vogelzang NJ, Egerdie B, et al. Radiographic Progression With Nonrising PSA in Metastatic Castration-Resistant Prostate Cancer: Post Hoc Analysis of PREVAIL. Prostate Cancer and Prostatic Diseases. 2017 Jan 24;20(1):51-59.
PSMA Imaging vs. Conventional Imaging
ESUR 2025. Opportunities for PSMA-PET/CT and Whole-Body MRI in Advanced Prostate Cancer. UroToday. December 19, 2025.
European Association of Urology 2025 Guideline on Advanced Prostate Cancer
Merseburger AS, Agarwal N, Bastos D, et al. Advanced and Metastatic Prostate Cancer: ESMO Clinical Practice Guideline for Diagnosis, Treatment and Follow-Up. Annals of Oncology. 2025 Aug;36(8):866-908.
https://www.annalsofoncology.org/article/S0923-7534(26)00042-6/fulltext
ASCO Living Guidelines for mCRPC (2026)
Taplin ME, Beltran H, Blumenthal G, et al. ASCO Issues First Living Guidelines for Prostate Cancer. Oncology News Central. February 3, 2026.
Patient Resource: PSA and Advanced Prostate Cancer
PSA and Advanced Prostate Cancer (2025 Guide). Malecare.org. Accessed May 2026.
https://malecare.org/advanced-prostate-cancer/psa-and-advanced-prostate-cancer/
Discordance Study: Bone Scan Index and PSA
Li J, Wang Y, Du C, et al. Discordance Between PSA Level and Bone Metastatic Volume Is Associated With Unfavourable Prognosis. Translational Oncology. 2025 Mar;48:102022.
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