Refining Biomarker Selection in Prostate Cancer

  • Biomarker testing is becoming foundational in prostate cancer, shifting care from clinicopathologic risk models to pathway-driven treatment selection.
  • PTEN loss is a common and clinically meaningful alteration, associated with more aggressive disease and emerging as a predictive marker for response to AKT pathway inhibition.
  • Depth of biomarker alteration matters for treatment decisions, with data suggesting high-level changes (e.g., ≥90% PTEN loss) are more likely to identify true pathway dependence and therapeutic benefit.
  • Implementation is increasingly practical across settings, as validated immunohistochemistry assays enable reliable biomarker detection without requiring full genomic sequencing.

As biomarker use in prostate cancer expands, PTEN loss is emerging as a critical therapeutic target for a subset of patients.

For years, prostate cancer lagged behind other solid tumors in the precision medicine race. Breast oncologists could look at a biopsy report and immediately glean ER, PR, and HER2 status, each one pointing toward a targeted therapeutic strategy. Prostate oncologists, meanwhile, worked largely from clinical and pathological variables (PSA, Gleason grade, stage) applying the same androgen deprivation playbook to a disease that is anything but uniform at the molecular level.

That is changing, and PTEN loss may be one of the most important reasons why.

“For years and years, we in the field of prostate cancer have been very envious of our breast cancer colleagues,”Dr. Eleni Efstathiou, GU Medical Oncologist and Prostate Cancer Researcher at the OHSU Knight Cancer Institute, told SurivorNet.

“They were able, right upon diagnosis, to get from a biopsy report about status of ER, PR, HER2 and other pathways that they can target and we were sitting there just being very basic. Well, guess what? This is changing and it’s changing fast.”

The Biology: Why PTEN Loss Matters

PTEN (phosphatase and tensin homolog) is a tumor suppressor gene whose job, simply put, is to act as a brake on cell growth. It does this by keeping a key signaling pathway (PI3K/AKT/mTOR) under control. When PTEN is lost, that brake is removed. The pathway runs unchecked, and the result is a cancer cell that is better at surviving, growing, and resisting treatment.”

It is the most commonly lost tumor suppressor in primary prostate cancer. Genomic deletion or mutation of PTEN is identified in approximately 15–20% of localized tumors at radical prostatectomy, rising to as high as 50% in castration-resistant disease. The association with adverse pathological features is well-established: PTEN loss correlates with higher Gleason grade, extraprostatic extension, earlier biochemical recurrence, and prostate cancer-specific mortality.

A meta-analysis of seven studies confirmed a strong correlation between PTEN genomic deletion and both elevated Gleason score and increased likelihood of extraprostatic extension.

From Prognostic to Predictive

The conceptual leap from prognosis to prediction requires understanding not just that PTEN is lost, but how much of it is lost and whether that loss is actually driving disease progression or simply along for the ride.

This distinction is something Dr. Efstathiou is direct about:

“When we’re looking at a cancer that is progressing, there may be a number of pathways that are present. The question is always which one is driving the progression. So if you see a little bit of loss of PTEN, we now know that it is not likely to be the driver of the progression.”

That nuance has translated into a specific clinical threshold in the most important recent trial in this space. In CAPItello-281, the global phase III study evaluating capivasertib (an oral, pan-AKT inhibitor) in combination with abiraterone and ADT, patients were required to have ≥90% PTEN loss by immunohistochemistry to be enrolled.

The rationale, as Dr. Efstathiou explains it: “The trials that were previously done that looked at the response that you had by targeting that pathway showed clearly that if there was a 90% or higher PTEN loss, you were likely to get a positive response when targeting that pathway.”

CAPItello-281: The Data

Presented at ASCO GU 2026, CAPItello-281 enrolled 1,012 patients with de novo metastatic hormone-sensitive prostate cancer (mHSPC) who met the ≥90% PTEN deficiency threshold. Patients were randomized 1:1 to receive capivasertib (400 mg twice daily on an intermittent 4-days-on/3-days-off schedule) plus abiraterone, prednisone, and ADT, versus placebo plus the same standard doublet.

The trial met its primary endpoint. Median radiographic progression-free survival (rPFS) was 33.2 months in the capivasertib arm versus 25.7 months in the control arm: an absolute improvement of 7.5 months (HR 0.81; 95% CI 0.66–0.98; p=0.034).

On tolerability, the most common on-target adverse events were:

  • diarrhea (approximately 52%)
  • hyperglycemia (38%)
  • and rash (35%).

Approximately 18% of patients discontinued capivasertib, most within the first three months, compared with 4.8% in the placebo arm. But quality of life data presented at GU ASCO 2026 provided some reassurance: physical well-being declined early (most pronounced in the first 6 to 12 weeks) but largely resolved by approximately three months, after which trajectories paralleled those of the control arm.

Dr. Efstathiou is candid about the toxicity trade-off:

“When it comes to the use of a drug like capivasertib, one needs to be careful as with all of those targeted agents. Indeed, they might be targeted, but they also come at some level of cost that might be translating into further compromise of the quality of life of patients.”

She specifically flags hyperglycemia as a management priority, given the higher baseline prevalence of metabolic syndrome in men on ADT.

“Monitoring is key for these agents. It is not for everyone. No drug is. And essentially it translates to that art of medicine within your practice to understand whether this drug is fitting the patient in the right way.”

Testing: The Immunohistochemistry (IHC) Advantage

For PTEN loss to function as a clinical biomarker, it needs to be measurable in a way that is accessible, reproducible, and practical across practice settings. Here, PTEN has a meaningful advantage over DNA damage response alterations, which typically require next-generation sequencing (NGS) sent to an external laboratory. Overall, IHC seems to correlate better with biological behavior and outcomes compared to NGS. It is important to realize that genomic and functional changes do not always align.

PTEN loss can be reliably detected by immunohistochemistry  (a platform available in virtually any hospital pathology department). Analytically validated IHC assays have been developed and used in clinical-grade settings with high interobserver reproducibility.

Dr. Efstathiou views this as a genuine clinical asset:

“Unlike what has been the case with DNA damage response mutation, it gives more independence and flexibility to the practice. So unlike other investigators who consider this to be somehow of a walk back in time, I find it to be a great thing because it gives the opportunity to everyone to have access to the assay.”

Regulatory Status and What Comes Next

Capivasertib (brand name Truqap) is currently FDA-approved for a subset of advanced or metastatic breast cancer patients. For prostate cancer, it is approval is under active FDA review, with the Oncologic Drugs Advisory Committee (ODAC) meeting scheduled for April 30, 2026. A decision is expected shortly thereafter.

“We are all waiting to hear from the FDA regarding the approval of this drug in this context,” Dr. Efstathiou says. “Having had this opportunity to review data that is coming from real world evidence in breast cancer patients, it makes us all feel more comfortable potentially using this drug.”

The Broader Message: Systematic Testing Cannot Wait

Regardless of when a formal approval arrives, Dr. Efstathiou’s core message to clinicians is that the infrastructure for molecular testing needs to be built now, not after the next positive trial, and not only at academic centers.

“The time is coming where there is no excuse to not offer to all patients testing that is based on molecular understanding of the disease,” she says.

“We have guidelines since 2017 that we should be offering both germline and somatic patient testing. I apologize to all patients that have advanced prostate cancer and I do not mean only metastatic; high risk, localized and beyond. So the time is coming where every practice needs to figure out a way to introduce systematic testing, not testing that is going to be on request. It’s going to be default.”

That shift, from reactive to systematic, from optional to standard, may be the most important step clinicians can take right now. The field of prostate oncology has spent decades building the evidentiary base.

PTEN as a predictive biomarker represents the moment that investment starts paying dividends in the clinic.

Dr. Rodrigo C. Leão Edelmuth is a board certified digestive surgeon at Hospital Israelita Albert Einstein in São Paulo, Brazil. He holds his General Surgery and Digestive Surgery degree from São Paulo University Medical School.

He underwent a postgraduate course on Surgical Leadership at Harvard Medical School and a Research Fellowship in the Department of Surgery at Weill Cornell Medicine in New York. Dr. Edelmuth is member of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and of the Society for Surgery of the Alimentary Tract (SSAT). In 2022 he received the SAGES Career Development Award.

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