Rising PSA after prostate cancer treatment can be worrying, especially when a PSMA PET scan is negative. The next step depends on the PSA level, how quickly it is rising, previous treatment and individual risk factors.
Who this is for
This article is for men who have undergone surgery or radiotherapy for prostate cancer and have recently been told that their PSA is rising again, despite a negative PSMA PET scan.
It explains when hormone therapy may help—and when careful monitoring may be more appropriate.
Clinical observation
I recently met a gentleman who had initially been diagnosed with Gleason score 9 prostate cancer, reported as 5+4.
This is considered a high-grade prostate cancer.
He underwent a radical prostatectomy and later received salvage radiotherapy after his PSA began rising again.
Following treatment, his PSA became undetectable and remained so for almost two years.
Last October, an ultrasensitive PSA test detected a value of 0.02 ng/mL.
Understandably, he became anxious that the cancer had already spread elsewhere in his body.
We arranged a PSMA PET scan. The scan showed no visible evidence of recurrent prostate cancer.
Three months later, his PSA had increased to 0.05 ng/mL.
These are both extremely low PSA values. Although the increase required further monitoring, a reliable PSA doubling time could not be established from only two very low readings.
His question was simple:
“If my PSA is rising but my scan is negative, do I already have metastatic prostate cancer? Should I start hormone therapy now?”
It is an excellent question and one that many men ask.
What surprised me
Perhaps the most important observation was that this patient would not have qualified for one of the major modern trials in this setting—the EMBARK trial.
For men who had undergone radical prostatectomy, EMBARK required:
- A PSA of at least 1.0 ng/mL
- A PSA doubling time of nine months or less
- No metastases detected on conventional CT and bone scans
- No further suitable curative salvage radiotherapy option
My patient’s PSA was only 0.05 ng/mL.
This was twenty times lower than the minimum PSA required after prostatectomy in EMBARK.
This creates an important question:
Should treatment begin as soon as an ultrasensitive PSA starts rising, or should we wait until the risk becomes clearer?
The honest answer is that EMBARK does not answer this question.
The trial showed that treatment helps carefully selected men with high-risk biochemical recurrence. It did not test whether starting treatment at a PSA of 0.05 ng/mL improves survival.
Starting treatment much earlier might help some patients, but it could also expose men to side effects for longer without a proven additional benefit.
Why this study matters
Until recently, men with a rising PSA after prostate cancer treatment were often:
- Monitored without immediate treatment, or
- Treated with androgen deprivation therapy alone
Androgen deprivation therapy, usually shortened to ADT, reduces the level or activity of testosterone that can stimulate prostate cancer cells.
The EMBARK trial asked an important question:
Can adding enzalutamide to ADT delay the development of metastatic disease and help men live longer?
For carefully selected men with high-risk biochemical recurrence, the answer was yes.
Understanding biochemical recurrence
After radical prostatectomy, PSA is expected to become undetectable because the prostate has been removed.
After radiotherapy without surgery, PSA usually falls gradually but may remain detectable because the prostate is still present.
A consistent rise in PSA after treatment can suggest that prostate cancer cells remain somewhere in the body.
This is called biochemical recurrence.
However, a rising PSA does not automatically mean that the cancer is metastatic.
Biochemical recurrence may occur months or years before cancer becomes visible on a scan.
At a PSA of 0.05 ng/mL, this patient had a very early ultrasensitive PSA rise. He had not yet reached the commonly used post-prostatectomy biochemical recurrence threshold of 0.2 ng/mL with a confirmatory result.
The upward trend was important, particularly because of his original high-grade cancer, but it still needed confirmation with further PSA testing.
Why can the PSA rise when the PSMA PET scan is negative?
PSMA PET is one of the most sensitive scans currently available for recurrent prostate cancer.
However, it cannot detect every microscopic group of cancer cells.
The chance of finding cancer on PSMA PET generally increases as the PSA rises.
In a recent study of patients with PSA levels of 0.2 ng/mL or lower, PSMA PET detected suspicious disease in approximately 30% of patients.
This means that most scans were negative at these very low PSA levels.
Therefore, a negative scan at a PSA of 0.02 or 0.05 ng/mL:
- Does not prove that the patient is cured
- Does not prove that the cancer is metastatic
- May simply mean that any remaining disease is too small to be seen
The result should be interpreted together with the PSA trend, previous treatments and original pathology.
The EMBARK trial
Study design
EMBARK was an international phase III randomised trial.
Number of participants
The trial included 1,068 men with high-risk biochemical recurrence.
Treatment groups
Participants were assigned to:
- Enzalutamide plus leuprolide: 355 men
- Enzalutamide alone: 355 men
- Leuprolide alone: 358 men
Leuprolide is a form of ADT.
Imaging used
Participants underwent conventional imaging with CT scans and bone scans.
PSMA PET imaging was not used to determine trial eligibility.
This is an important limitation when applying the results today.
Who qualified for EMBARK?
Participants needed a PSA doubling time of nine months or less.
They also needed one of the following:
After radical prostatectomy
- PSA of at least 1.0 ng/mL
This included men who had also received postoperative or salvage radiotherapy.
After radiotherapy without prostatectomy
- PSA of at least 2.0 ng/mL above the lowest PSA reached after radiotherapy
Participants also had to have no metastatic disease visible on conventional imaging and could not be suitable for further curative salvage radiotherapy.
A unique feature of EMBARK
Treatment did not necessarily continue without a break.
Participants initially received treatment for 36 weeks.
If the PSA was below 0.2 ng/mL at week 36, treatment was suspended at week 37.
Treatment restarted when the PSA increased to:
- At least 2.0 ng/mL for men who had undergone prostatectomy
- At least 5.0 ng/mL for men who had not undergone prostatectomy
This planned treatment break reduced the amount of time some men spent receiving therapy.
However, it should not be assumed that every patient will be suitable for the same approach outside a clinical trial.
Key results
Remaining alive without visible metastatic disease
At five years, the proportion of men who were alive without metastases detected on conventional imaging was:
- 87.3% with enzalutamide plus ADT
- 71.4% with ADT alone
- 80.0% with enzalutamide alone
In patient terms, for every 100 men treated:
- Approximately 87 receiving enzalutamide plus ADT were alive without visible metastases at five years.
- Approximately 71 receiving ADT alone were alive without visible metastases.
This was an absolute difference of approximately 16 men out of every 100 treated.
Enzalutamide plus ADT produced a 58% relative reduction in the risk of metastasis or death compared with ADT alone.
Enzalutamide alone produced a 37% relative reduction.
These relative reductions describe what happened across the study population. They do not mean that every individual patient receives the same amount of benefit.
Overall survival
With longer follow-up, the eight-year overall survival results were:
- 78.9% with enzalutamide plus ADT
- 69.5% with ADT alone
This was an absolute difference of approximately 9.4 percentage points.
In simpler terms, among 100 men similar to those in EMBARK, approximately nine additional men were alive at eight years after receiving enzalutamide plus ADT rather than ADT alone.
The hazard ratio was 0.60, representing an approximately 40% relative reduction in the risk of death during the study period.
This does not mean that every patient lived 40% longer.
Enzalutamide alone
Eight-year overall survival was:
- 73.1% with enzalutamide alone
- 69.5% with ADT alone
This difference was not statistically significant.
Therefore, the strongest survival evidence currently supports enzalutamide combined with ADT rather than enzalutamide alone.
What about side effects?
The benefit of earlier treatment must be balanced against its effects on quality of life.
Common side effects of enzalutamide combined with ADT included:
- Hot flushes
- Fatigue
- Reduced sexual function
- Changes in blood pressure
- Falls or fractures in some patients
Enzalutamide alone was more commonly associated with breast enlargement or breast tenderness.
The appropriate treatment depends not only on PSA results but also on:
- Age
- Heart and bone health
- Risk of falls
- Other medicines
- Previous treatment
- Personal priorities
- Willingness to accept treatment side effects
How does this apply today?
Modern imaging has changed prostate cancer care.
EMBARK used CT scans and bone scans. These are less sensitive than PSMA PET.
Some men considered non-metastatic in EMBARK might have small areas of disease detected by PSMA PET today.
However, the opposite situation also occurs.
Some men have a rising PSA but a completely negative PSMA PET scan because their PSA remains too low for the cancer to be located reliably.
Current European guidance recommends enzalutamide with ADT for men who resemble the EMBARK population:
- No metastases on conventional imaging
- PSA doubling time of nine months or less
- PSA above the trial-defined threshold
- No suitable curative salvage treatment remaining
The evidence is less certain for men whose PSA remains far below those thresholds.
What I discussed with my patient
His PSA had increased from 0.02 to 0.05 ng/mL.
This needed to be taken seriously because of his original high-grade prostate cancer and previous biochemical recurrence.
However:
- His absolute PSA remained extremely low.
- His negative PSMA PET scan was not unexpected at such a low PSA.
- His PSA remained far below the 1.0 ng/mL threshold used after prostatectomy in EMBARK.
- The trial does not show that beginning ADT and enzalutamide at a PSA of 0.05 ng/mL improves survival.
A reasonable approach was therefore:
- Repeat the ultrasensitive PSA, preferably through the same laboratory
- Confirm that there was a consistent upward trend
- Calculate the PSA doubling time using several results
- Review the original pathology and previous radiotherapy details
- Consider repeating PSMA PET later if the PSA continued to rise and the result would alter treatment
- Reassess the benefits and side effects of systemic treatment as more information became available
The decision to begin ADT or enzalutamide should be individualised rather than based on one very low PSA result alone.
Key takeaways
- A rising PSA does not automatically mean metastatic prostate cancer. Cancer may remain too small to appear on even a sensitive PSMA PET scan.
- A negative PSMA PET scan at a very low PSA does not prove that no cancer remains. The likelihood of detecting recurrence generally increases as the PSA rises.
- EMBARK changed treatment for high-risk biochemical recurrence. Enzalutamide plus ADT improved five-year metastasis-free survival and eight-year overall survival in men who met specific high-risk criteria.
- EMBARK does not prove that treatment should begin at a PSA of 0.05 ng/mL. Repeat PSA measurements, PSA doubling time, previous treatments, imaging findings and quality-of-life considerations should guide the decision.
Key evidence
- Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465. doi:10.1056/NEJMoa2303974
- Shore ND, de Almeida Luz M, De Giorgi U, et al. Improved survival with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2026;394(6):563-575. doi:10.1056/NEJMoa2510310
- Spratt DE, An Y, Bitting R, et al. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 5.2026. National Comprehensive Cancer Network; 2026. Accessed July 28, 2026. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459
- European Association of Urology. EAU Guidelines on Prostate Cancer. 2026 edition. Accessed June 26, 2026. https://uroweb.org/guidelines/prostate-cancer
- Burgard C, Frei M, Blickle A, et al. PSMA PET/CT in biochemical recurrence of prostate cancer with PSA levels ≤0.2 ng/mL: a German multicentre analysis of conventional PSMA tracers. Eur J Nucl Med Mol Imaging. 2025;52:4368-4376. doi:10.1007/s00259-025-07292-1
Frequently asked questions (FAQs)
- My PSMA PET scan is negative. Does that mean I am cured?
Not necessarily.
Very small deposits of prostate cancer may remain below the detection limit of the scan, particularly when the PSA is extremely low.
A negative scan is useful information, but it must be interpreted together with the PSA trend and previous treatment history.
- Does a rising PSA always mean I need hormone therapy?
No.
The decision depends on:
- The PSA level
- How quickly the PSA is rising
- Previous surgery and radiotherapy
- Imaging findings
- Original cancer grade
- General health
- Potential treatment side effects
- Personal preferences
Some men benefit from monitoring before beginning treatment.
- Would I have qualified for the EMBARK trial?
Following prostatectomy, you would generally have needed:
- PSA of at least 1.0 ng/mL
- PSA doubling time of nine months or less
- No metastases on CT or bone scan
- No remaining suitable curative salvage radiotherapy option
Following radiotherapy without prostatectomy, the PSA needed to be at least 2.0 ng/mL above the lowest PSA reached after treatment.
- Should I have a PSMA PET scan if my PSA is rising?
Not necessarily immediately.
PSMA PET becomes more likely to detect recurrent cancer as the PSA increases.
After prostatectomy, current European guidance suggests considering PSMA PET when PSA is above 0.2 ng/mL if the result would change treatment.
Earlier scanning may sometimes be considered, but patients should understand that a negative result is common at very low PSA levels.
Dr Dilanka De Silva
MBBS, MRCP(UK), MRCP(UK SCE Oncology), FRACP, PhD
Medical Oncologist & Cancer Genetics Physician
Memorial Sloan Kettering Cancer Center Fellow (New York, USA)