When Cancer Moves Without Warning:
The Prognostic Significance of Radiographic Progression Without PSA Progression in Patients With Metastatic Hormone‐Sensitive Prostate Cancer Treated With First‐Line ARPI Therapy - Tsutsumi - The Prostate - Wiley Online Library
Vol. 28 / Treatment Monitoring
The Problem of PSA-Silent Progression
A new study from Japan, along with a growing body of international research, reveals that a significant number of men on today's powerful hormone therapies can have cancer that spreads on imaging — even while their PSA levels look perfectly controlled. What does this mean for how you are being monitored?
A critical gap in standard prostate cancer monitoring has been confirmed by multiple major studies: roughly 1-in-14 men on today's most effective hormone therapies (called ARPIs) will see their cancer grow on scans while their PSA blood test continues to look normal. This "PSA-silent" or "discordant" progression is not a minor anomaly — these patients have significantly shorter survival after their cancer becomes resistant. The data clearly show that PSA monitoring alone is no longer sufficient for men on ARPI-based therapy. Regular imaging scans are needed, even when PSA appears well controlled.
- In a multicenter Japanese study, 6.6% of men on ARPI therapy progressed radiographically with no PSA rise — and had a median overall survival of only 21 months after starting treatment, versus 39 months for those who progressed via PSA alone.
- Multiple large clinical trials — TITAN, ARCHES, and CHAARTED — have all independently confirmed this phenomenon.
- High-volume disease is the single strongest predictor of who will experience this "silent" progression.
- The biological culprit is likely a shift toward an aggressive, PSA-independent cancer cell type, sometimes called neuroendocrine or androgen-receptor-independent disease.
- PCWG3 guidelines already recommend imaging every 8–12 weeks in clinical trials; real-world practice needs to catch up.
What Is "PSA-Silent" Progression — and Why Does It Matter to You?
If you are being treated for metastatic hormone-sensitive prostate cancer (mHSPC) — meaning cancer that has spread but still responds to testosterone-lowering therapy — your doctor almost certainly monitors your PSA on a regular basis. PSA, or prostate-specific antigen, has been the cornerstone of prostate cancer surveillance for decades. When it rises, we worry. When it falls or stays low, we breathe easier.
But a substantial and growing body of research is now challenging that reassuring logic — at least for men who are on the newer, more powerful classes of hormone therapy called androgen receptor pathway inhibitors, or ARPIs. These include drugs many of you know by name: abiraterone (Zytiga/Yonsa), enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa).
These medications are extraordinarily effective at suppressing PSA. That is largely why they work so well. But herein lies a paradox: by doing such a thorough job of suppressing the androgen-driven, PSA-secreting cells in the tumor, they may allow a different, more dangerous population of cancer cells — ones that do not depend on male hormones and do not produce much PSA — to quietly multiply and spread. The cancer can be growing on your CT scan or bone scan even as your PSA number looks reassuringly low.
This is called radiographic progression without PSA progression — or informally, "PSA-silent" or "discordant" progression. It is not a new concept, but its full clinical importance is only now coming into sharp focus, thanks to a series of high-quality studies published in 2024 and 2025.
The Japanese Multicenter Study: Key New Evidence
The most detailed recent examination of this issue comes from a newly published Japanese multicenter study involving 518 men with metastatic hormone-sensitive prostate cancer treated with first-line ARPI therapy at seven major university hospital networks across Japan, including Kindai University Hospital, Jikei University, and five others. The study was recently published in a peer-reviewed urology journal and provides the clearest real-world look yet at just how common and serious this problem is.
Of the 518 patients followed over a median of 21 months, 169 (32.6%) developed castration-resistant prostate cancer (CRPC). Within that group, 135 progressed via PSA elevation, while 34 men — that's 6.6% of the entire cohort — progressed radiographically with no PSA rise at all. Every single one of these cases was detected through regularly scheduled CT scans, not because patients had symptoms.
The prognosis for the PSA-silent group was striking. Their median overall survival from the start of ARPI treatment was only 21 months, compared to 39 months for those who progressed via PSA. Once their cancer became castration-resistant, survival after that point was only 7 months on average, versus 19 months for PSA-progressors. These are not small differences.
Perhaps most counterintuitive: the men who eventually developed PSA-silent progression were actually the best responders by PSA metrics. Their PSA nadir during initial treatment was a remarkably low median of 0.055 ng/mL, compared to 0.86 ng/mL in those who later progressed with a PSA rise. More than 61% achieved a nadir below 0.2 ng/mL, versus only 27% in the PSA-progression group. Their PSA responses looked excellent — yet their cancer was escaping.
This Is Not an Isolated Finding: What the Major Clinical Trials Tell Us
The Japanese study is the latest in a series of convergent findings from the world's largest prostate cancer trials. When researchers went back and looked specifically at what happened to patients who developed radiographic progression in these landmark studies, the pattern was consistent and troubling.
The TITAN Trial (Apalutamide)
In a secondary analysis of the TITAN trial — the large Phase III study that established apalutamide as a standard-of-care treatment — researchers examined the 115 men on apalutamide who developed radiographic progression. An extraordinary 52.2% of them had progression on scans without corresponding PSA progression, compared to just 27.5% in the placebo group. Apalutamide treatment itself was independently associated with this discordant pattern. These patients were more likely to have visceral (organ) metastases and had worse radiographic outcomes despite having what looked like favorable PSA control. This key finding was published in European Urology Oncology in 2024–2025.
The ARCHES Trial (Enzalutamide)
In a post-hoc analysis of the ARCHES trial — which validated enzalutamide in metastatic hormone-sensitive disease — researchers found that 67% of enzalutamide-treated patients who developed radiographic progression had no PCWG2-defined PSA progression at the time their scans showed disease activity. In contrast, only 43% of placebo-treated patients had this discordance. The median PSA at the time of radiographic progression in the enzalutamide arm was just 2.25 ng/mL — a level most clinicians would not consider alarming. The investigators concluded that serial PSA monitoring alone is not sufficient to detect radiographic progression in patients on enzalutamide.
The CHAARTED Trial (Docetaxel in mHSPC)
Even in the earlier CHAARTED trial, which tested docetaxel in hormone-sensitive metastatic disease (before the ARPI era), clinical progression without a PSA rise was found in approximately 25% of patients. Notably, this PSA-silent progression pattern was more common in men with low-volume disease (44.8%) than high-volume disease. Patients who progressed clinically without a PSA rise had inferior overall survival from the start of therapy, establishing this as a broader phenomenon not limited to ARPI treatments.
The PREVAIL Trial (Enzalutamide in mCRPC)
In metastatic castration-resistant prostate cancer, a post-hoc analysis of the PREVAIL trial found that 24.5% of men on enzalutamide progressed radiographically without a PSA rise. Patients with lung or liver (visceral) metastases had an even higher rate of discordance, at 34.4%. These patients had worse progression-free survival outcomes than those whose PSA and scans moved together.
In standard monitoring, we expect PSA and cancer activity on imaging to move together — when one rises, the other follows. "Discordant progression" (also called PSA-silent or radiographic-only progression) is when CT scans or bone scans show new or growing cancer lesions, but PSA either stays low, does not rise by the threshold required to call it "progression," or even continues to fall. It is called "discordant" because the two measures are telling different stories.
Most recently, the 2026 ASCO Genitourinary Cancers Symposium included a dedicated session on evaluating progression endpoints, where multiple experts emphasized the growing disconnect between PSA and imaging-defined progression across the major ARPI trials. Expert commentary confirmed that discordant progression carries a similarly poor prognosis to combined PSA-and-radiographic progression, reinforcing the need for updated monitoring guidelines.
Why Does This Happen? The Biology of Escape
Understanding why this happens requires a brief look at how prostate cancer evolves under treatment pressure. Most prostate cancer cells depend on male hormones (androgens) to grow and survive — and they also happen to produce PSA as a byproduct of that hormonal activity. When ARPIs block androgen signaling effectively, these cells shrink or stop growing, and PSA falls.
But advanced prostate tumors are not a single uniform population of cells. They are a mixed ecosystem. Within a tumor, there are subpopulations of cells that have already evolved or are capable of evolving to grow without androgen stimulation. When the powerful ARPIs suppress all the androgen-dependent cells, these "escape artist" clones gain an evolutionary advantage and expand.
The most well-characterized escape mechanism is called neuroendocrine differentiation — a process in which prostate cancer cells change their identity to resemble cells of the nervous system, which have no need for androgen signaling and produce little or no PSA. A 2025 meta-analysis found that neuroendocrine transformation after ARPI therapy occurs in approximately 16% of patients with metastatic castration-resistant disease — and it is frequently underdiagnosed because it requires biopsy to confirm and is not reflected in routine PSA testing. Another recent analysis estimated that over 30% of patients at advanced stages after ARPI treatment may develop some neuroendocrine characteristics.
- ~16% frequency of neuroendocrine transformation after ARPI therapy per 2025 meta-analysis
- 10× higher odds of PSA-silent progression in high-volume vs. low-volume disease (Japanese study multivariate analysis)
- 52% of apalutamide-treated patients who progressed radiographically had no PSA progression (TITAN trial)
Beyond neuroendocrine differentiation, researchers have identified several genomic "keys" that seem to unlock this PSA-independent growth, including loss of tumor suppressor genes TP53, RB1, and PTEN. These alterations promote what scientists call "lineage plasticity" — the cancer cell's ability to change its identity to escape treatment. The 2025 ESMO Congress included dedicated sessions exploring these mechanisms, with researchers developing new therapeutic strategies specifically targeting cells that have undergone this lineage switch.
A study from the University of Turin published in Cells (2024) also confirmed that the presence of neuroendocrine differentiation in mCRPC was associated with significantly worse outcomes when patients were treated with enzalutamide or abiraterone — reinforcing that these PSA-silent disease variants do not respond well to continued ARPI-based therapy.
Who Is Most At Risk?
The Japanese multicenter study is particularly valuable because it specifically identified who is most likely to experience PSA-silent progression. In a multivariate analysis — meaning they accounted for all the other factors simultaneously — high-volume disease by the CHAARTED criteria was by far the strongest predictor.
The CHAARTED definition of high-volume disease means: the presence of visceral metastases (spread to organs like the lung or liver) OR four or more bone metastases with at least one outside the spine and pelvis. Men with high-volume disease had 10 times the odds of developing PSA-silent progression compared to those with low-volume disease. In the PSA-silent group, 94.1% had high-volume disease, compared to 77.8% of those who progressed via PSA elevation.
- You have high-volume disease: 4 or more bone metastases (with one outside spine/pelvis) or visceral metastases (lung, liver)
- You have achieved a very deep PSA response — a nadir below 0.2 ng/mL — on your current ARPI therapy
- You have visceral metastases, particularly soft-tissue lesions
- You are on apalutamide (Erleada), which appears to produce discordant progression at a higher rate than placebo
If any of these apply to you, ask your oncologist specifically about your imaging surveillance schedule.
What This Means for Your Care: The Monitoring Gap
The current standard in many real-world practices is to order imaging primarily when PSA rises or when you develop symptoms. In this model, a man whose PSA is beautifully controlled at 0.04 ng/mL might not get a CT scan for a year or more — even while cancer is growing silently in his lymph nodes or bones.
The Prostate Cancer Working Group 3 (PCWG3) guidelines — the standard-setting framework for clinical trials — already recommend radiographic assessments every 8 to 12 weeks in clinical trial settings, particularly when there are symptoms or signs of PSA-incongruent progression. The authors of the Japanese multicenter study explicitly call for extending this principle to real-world clinical practice:
This is not a fringe opinion. At the January 2026 ASCO Genitourinary Cancers Symposium, Dr. Andrew Armstrong of Duke University presented a comprehensive review of progression endpoints in which he underscored the same point: "Serial PSA monitoring alone may not be sufficient to detect radiographic progression in many patients" on potent ARPIs.
In practical terms, this means patients and their advocates need to have a direct conversation with their oncology team about imaging frequency. The question to ask is straightforward: "Given that I am on an ARPI and the research shows PSA can look normal while cancer spreads, what is our imaging plan — and how often are we scanning?"
What Happens When PSA-Silent Progression Is Detected?
The Japanese study found that patients with PSA-silent progression were less likely to receive certain subsequent treatments and had significantly shorter survival after their cancer became resistant. At the time of radiographic progression in these patients, bone metastases were found in 64.7% and visceral metastases in 23.5% — considerably more than in the PSA-progression group.
Treatment options at this stage remain largely the same as for PSA-defined CRPC: docetaxel chemotherapy, PSMA-targeted radioligand therapy (Pluvicto/lutetium-177 PSMA-617), PARP inhibitors for those with HRR gene mutations, and clinical trials. The key difference is that because PSA-silent progression often reflects an androgen-receptor-independent tumor, further escalation of AR-directed therapy may be less useful, and treatment should ideally be guided by biopsy and molecular profiling where possible.
A concern with neuroendocrine and PSA-silent disease is that these cancer cells often lose PSMA expression as they shift away from typical prostate cancer biology. This could theoretically limit the benefit of Pluvicto (lutetium-177 PSMA-617). However, the landmark Phase III PSMAddition trial — presented at ESMO 2025 — demonstrated that adding lutetium-177 PSMA-617 to standard ARPI + ADT therapy in hormone-sensitive metastatic prostate cancer significantly improved radiographic progression-free survival (HR 0.72, p=0.002), reducing the risk of progression or death by 28%. Benefit was seen across all subgroups including high-volume disease. Novartis has announced plans to submit these data for regulatory approval — which could eventually make this triple-therapy available much earlier in disease treatment, potentially before PSA-silent progression becomes an issue.
The Emerging Role of Advanced Imaging and Liquid Biopsy
Beyond conventional CT and bone scans, researchers are actively investigating better tools to detect and characterize early resistance — tools that would not rely on PSA at all. Among the most promising:
PSMA PET/CT Imaging: PSMA PET scanning (using gallium-68 or fluorine-18 labeled PSMA agents) is dramatically more sensitive than standard imaging and can detect lesions years earlier. It is already FDA-approved for staging at diagnosis and for detecting recurrence. Its role in routine monitoring of men on ARPI therapy is an active area of investigation. Importantly, PSMA PET can also detect when tumors are beginning to lose PSMA expression — a warning sign of neuroendocrine transformation.
FDG-PET: When PSMA expression is lost, tumors often become detectable by FDG-PET, which measures glucose metabolism rather than PSMA. Combining PSMA-PET and FDG-PET can help characterize the full extent of disease in patients with heterogeneous tumors, some of which have undergone neuroendocrine transformation.
Circulating Tumor DNA (ctDNA): A simple blood test that detects fragments of tumor DNA shed into the bloodstream, ctDNA can identify key genomic alterations — including TP53 and RB1 loss — that signal aggressive, PSA-independent disease. Multiple presenters at ESMO 2024 and 2025 highlighted ctDNA as a highly prognostic tool that can identify which patients are at highest risk, even before clinical or radiographic signs appear.
These advanced tools are not yet standard of care in routine monitoring, but they represent the direction of travel. If you are on ARPI therapy and have high-volume disease or other risk factors, asking about PSMA PET at your next restaging assessment is a reasonable and well-supported conversation to have with your physician.
What You Should Discuss With Your Doctor
The body of evidence summarized here carries practical implications for anyone receiving ARPI-based therapy for metastatic hormone-sensitive prostate cancer. Here are the key questions to bring to your next appointment:
- "Do I have high-volume or low-volume disease?" — This is the single strongest risk factor for PSA-silent progression.
- "What is my imaging surveillance schedule?" — Ask specifically how often you will be getting CT scans and bone scans, and whether that schedule would change if your PSA remains low.
- "Should I be getting PSMA PET scans as part of my monitoring?" — Especially relevant if you had high-volume disease at diagnosis.
- "Has my tumor been tested for TP53, RB1, or PTEN alterations?" — These genomic markers are associated with higher risk of lineage plasticity and PSA-silent progression.
- "If my scans show progression but my PSA is normal, what is the plan?" — Having a contingency plan discussed in advance is valuable.
- "Would I be a candidate for a biopsy of a progressing lesion?" — Tissue biopsy at progression can guide treatment by identifying neuroendocrine features or specific genomic alterations.
The Bottom Line for Patients
The good news: the research community has clearly identified this problem and is actively working to address it — both through improved monitoring guidelines and through new therapies that may prevent or treat PSA-silent resistance. The PSMAddition trial results, the TITAN and ARCHES post-hoc analyses, the emerging ctDNA and PSMA PET data, and the Japanese real-world cohort study all tell a coherent story that the field is taking seriously.
The challenge: real-world clinical practice has not yet fully caught up with what the trial data are showing. In busy oncology clinics, imaging is still too often triggered only by PSA rises or symptoms. Patients with excellent PSA responses may go many months without a scan — which is precisely the population that may need surveillance most.
Informed, empowered patients who ask the right questions are the most important force in closing that gap. If you or your loved one is on ARPI therapy for metastatic prostate cancer, this is the time to have a frank conversation about what a truly comprehensive monitoring plan looks like in the modern era of prostate cancer care.
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