FDA Approves First-of-its-Kind Drug For Advanced Prostate Cancer With Common PTEN Deficiency Mutation

The approval is significant because it gives patients and doctors a new tool that’s been shown to slow cancer progression — and because of how the drug works.

“This is first-in-class mechanism of action for a drug approval in prostate cancer,” Dr. Russell Pachynski, GU oncologist at Siteman Cancer Center in St. Louis, tells SurvivorNet. “The more different ways we can hit the prostate cancer, the better.”

Why PTEN Deficiency Matters

PTEN is a protein. Its job is to act as a brake on cancer cell growth. When a tumor loses this protein, or stops producing enough of it, that brake disappears.

A signaling pathway called PI3K/AKT then gets switched on, and cancer cells keep dividing. They do this even when standard hormone therapies are actively trying to stop them. The result is a more aggressive disease that tends to progress faster and respond less well to treatment.

“Be aware of PTEN as a really bad actor,” says Dr. Neal Shore of Carolina Urologic Research Center. “Patients with PTEN deficiency have a very poor prognosis — and it’s worth everyone’s attention.”

Roughly one in four men with metastatic hormone-sensitive prostate cancer carry this flaw. That translates to about 35,000 men diagnosed in the United States every year. For these patients, the standard treatments (androgen deprivation therapy combined with drugs like abiraterone) haven’t worked as well as they do for men whose tumors still have functioning PTEN.

Capivasertib targets that gap. By blocking AKT, it shuts down the alternative growth pathway that PTEN deficiency throws open. Paired with abiraterone, which attacks the androgen receptor pathway, the two drugs hit prostate cancer from two completely different directions at once.

Capivasertib Shows Promise in Trial

The approval was based on results from the CAPItello-281 trial.

This was a large, rigorous phase III study that involved 1,012 men from 32 countries who were newly diagnosed with PTEN-deficient metastatic hormone-sensitive prostate cancer.

Half received capivasertib plus abiraterone and half received placebo plus abiraterone.

The primary goal was to measure how long patients went before their cancer showed signs of growth on imaging. That’s called radiographic progression-free survival.

The results clearly favored capivasertib:

• Men on capivasertib plus abiraterone went a median of 33.2 months before their cancer progressed compared to 25.7 months for men on abiraterone alone — a 7.5-month difference.
• The difference translates to a statistically significant 19% reduction in the risk of disease progression or death.
• Among men whose tumors had the most complete loss of PTEN (meaning zero detectable PTEN protein in any cancer cell) the risk reduction climbed to 32%.

Dr. Pachynski called this pattern particularly compelling.

“At even higher levels of PTEN loss, they saw an increase in clinical benefit in those patients — that’s something we call a ‘dose-response,'” he explains. “And really supports this mechanistic link as being clinically important.”

However, this particular finding wasn’t part of the original trial plan. Researchers looked at it after the main results came in. It’s encouraging, but it needs to be confirmed in future studies before doctors can treat it as settled science.

At the time of this analysis, the overall survival data, or data that shows whether this drug actually helps men live longer, were not yet mature enough to draw conclusions. The trial is ongoing. The approval was based on the progression-free survival benefit.

“We still don’t have data to show that this improves overall survival,” Dr. Pachynski notes. “So I think that’s an important caveat — but we may, in time, see that a subset of these biomarker-selected patients do, in fact, have longer overall survivals.”

Side Effects: What Patients Should Know

As with any cancer treatment, it’s important for patients to understand the risk of side effects.

The most common side effects associated with capivasertib in the trial were:

• Diarrhea (seen in about 52% of patients)
• Skin rash (seen in about 35% of patients)
• Elevated blood sugar, aka hyperglycemia (seen in about 38% of patients)

Most cases were manageable. The majority of diarrhea was mild to moderate, and over 90% of those patients had recovered or were recovering by the time the data were analyzed.

Additionally, serious adverse events occurred in 42% of the capivasertib group, compared to 26% of patients on abiraterone alone.

Around 18% of patients ultimately stopped taking capivasertib because of side effects, and that’s only part of the picture. A separate 63% required a dose interruption or reduction at some point during treatment. Most people stayed on the drug, but nearly two-thirds needed it adjusted.

These are drugs patients may be taking for years, so understanding risks is key.

“As clinicians, we really have to be cognizant about the risk/benefit ratios — really important discussion to have with patients,” Dr. Pachynski adds.

Testing For PTEN Deficiency

The part that matters most for patients is that the benefit of capivasertib has only been demonstrated in those who have PTEN deficiency.   “PTEN testing should be performed at routine metastatic diagnosis, ideally via IHC,” says Dr. Neal Shore.   The drug is approved only for patients who test positive, and that requires a specific test that must be ordered by your doctor.

The FDA approved a companion diagnostic alongside the drug: the VENTANA PTEN (SP218) assay. It’s an immunohistochemistry test, performed on tumor tissue from a biopsy. It identifies whether PTEN protein is absent from cancer cells. Without it, there’s no way to know if a patient qualifies.

Dr. Pachynski sees this as a turning point, not just for capivasertib, but for how physicians should approach every prostate cancer diagnosis going forward.

“Each prostate cancer is unique to each patient, and is constantly changing in response to each treatment,” he explains. “We really need to encourage providers to do this type of testing not only at diagnosis, but throughout the patient’s prostate cancer journey.”

If you or someone you love has metastatic prostate cancer and comprehensive biomarker testing hasn’t been done, that conversation needs to happen with your oncologist as soon as possible.

A test result that unlocks a treatment option is worthless if no one orders the test.

The Bigger Picture

Prostate cancer treatment has changed enormously over the past decade resulting in new drugs, new combinations, and more options. But those options have mostly worked through the same basic mechanism — suppressing male hormones, blocking the androgen receptor, and starving the cancer of what it needs to grow.

Capivasertib does something genuinely different. It targets a separate biological pathway that, in PTEN-deficient tumors, has been running unchecked.

“The field has — rightfully so — targeted AR for a long time,” Dr. Pachynski says. “But there are many different ways prostate cancer can escape androgen dependence. Exploring and exploiting these different mechanisms is of critical importance to move the field forward.”

He put it simply at the start of our conversation: any time patients get a new, effective option — that’s a good thing.

Questions To Ask Your Doctor

• Have I been tested for PTEN deficiency?
• Should I consider/am I able to add capivasertib to my treatment plan?
• What side effects should I be aware of?
• Are there clinical trials I should know about that might give me access to additional targeted treatments based on my tumor’s biology?

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