Behind the FDA approval of capivasertib for mHSPC, with Daniel J. George, MD

The treatment landscape for metastatic hormone-sensitive prostate cancer (mHSPC) continues to evolve with the incorporation of biomarker-driven therapeutic strategies. On June 12, 2026, the FDA approved capivasertib (Truqap) in combination with abiraterone acetate (Zytiga) and prednisone for adult patients with PTEN-deficient metastatic androgen pathway modulation-naïve or sensitive (mAPMN/S) prostate cancer, previously mHSPC, marking the first approved treatment specifically targeting this molecularly defined subset of disease.^1,2 PTEN loss, which occurs in approximately one-quarter of patients with metastatic prostate cancer, is associated with activation of the PI3K/AKT signaling pathway and has long been recognized as a poor prognostic factor.

The approval was supported by findings from the phase 3 CAPItello-281 trial (NCT04493853), which demonstrated a statistically significant improvement in radiographic progression-free survival (rPFS) with the addition of capivasertib to standard therapy.³ Patients treated with the triplet regimen achieved a median rPFS of 33.2 months compared with 25.7 months for those receiving abiraterone and prednisone alone. The study also showed favorable trends across several secondary end points, including time to castration resistance and symptomatic skeletal event–free survival.

In this interview, Daniel J. George, MD, of Duke Health, discusses the clinical significance of the approval, practical considerations for PTEN testing and toxicity management, and the broader implications of precision medicine for patients with advanced prostate cancer.

Urology Times: What is the significance of this approval for the treatment landscape, and what unmet need does it address for patients with PTEN-deficient disease?

George: We've known for 30 years that the loss of PTEN, particularly in prostate cancer, is one of the most common genetic defects that we find. It has negative prognostic significance; these patients have worse outcomes because of it. Despite a number of efforts, we've, up until recently, not been able to drug this pathway to find a way to block it. PTEN deficiency is essentially a loss of a break. PTEN is a tumor suppressor gene, and when you lose it, it results in the overactivation of a pathway called PI3K/AKT, and these are 2 signal transduction proteins involved in sending signals from the cell surface to the nucleus to activate the cells. This pathway is independent of the testosterone or androgen receptor pathway. It's a second growth signal, a second survival signal for the cancer cells that that we've left alone in our treatment of prostate cancer up until this time.

Urology Times: This approval was based on the CAPItello-281 trial, which demonstrated a median rPFS benefit of 33.2 months vs 25.7 months. How clinically meaningful do you view that improvement, and how should urologists be interpreting these results in practice?

George: In this study, we focused on patients with de novo mAPMN disease, so these are patients that are presenting with stage 4 prostate cancer. On their biopsies, largely prostate biopsies, they were found to have 90% or greater loss of the PTEN protein, so deemed PTEN deficient. We screened 6200 patients. We found about 1500 patients that met that criteria, and about 1000 patients were [randomly assigned] 1:1 to standard of care abiraterone, prednisone, and ADT, or abiraterone, prednisone, and capivasertib. It was placebo-controlled, and patients were followed until death, disease progression, or unacceptable toxicity. rPFS assessed by the investigator was a primary end point.

The study met its primary end point; it improved rPFS by 7.5 months. There was a 33.2-month median rPFS in the treatment arm. In the control arm, our standard of care of abiraterone, ADT, and prednisone, had a 25.7-month median rPFS. That's important to recognize, because that is much lower than what we see in our other clinical trials, which are 36 months or higher in many cases. This really validates, for the first time prospectively, in a big international multicenter study, that this is a bad subset of disease. These patients have more rapid progression.

If you look at overall survival, among patients in that abiraterone/ADT arm, what we consider standard of care, 30% are dead in just 2 years. This is a significant portion of this population that's at risk for early death, higher rates of symptomatic skeletal events, early time to castration resistance, and a much earlier time to subsequent chemotherapy. These reasons exemplify why this is a population we need to know about, and why the standard of care is not enough. And 7.5 months for patients delaying that first progression is meaningful. That's what came out of our [Oncologic Drugs Advisory Committee] meeting. Sure, we like to see bigger treatment effects, and maybe there's a tail of this curve that's going to show a bigger treatment effect for a subpopulation. But overall, in this bad PTEN deficient population, we're seeing this significant improvement, and that is progress for our patients.

Urology Times: Thinking about the safety profile for this regimen, what strategies can urologists use to monitor for and manage toxicities?

George: The key thing I would stress to my urology colleagues is to be proactive around these toxicities. These are all toxicities that are well known. Hyperglycemia is something that we have managed for decades now. This is not diabetes; this is hyperglycemia by blocking the AKT pathway. It's important for urologists to know that this is an on-target treatment effect that reverses when you stop the drug. We dose this drug for 4 days and then 3 days off, and during those 3 days, the blood glucose is going to come down. In the study, when patients did go on insulin, the average time on insulin was 8 days. These patients came off very quickly, because the effects of the drug on this pathway are reversible.

The same thing is true with diarrhea. In patients experiencing this, you hold the drug and it washes out, and we're stopping 3 out of 7 days anyway, so you have that built in. Additional interruptions are something that we shouldn't be afraid to use, especially early on, until we get a handle of these [adverse events]. The average onset of these [adverse events] is 2 weeks, so some of these patients experience it within their first 4 days on the drug. I like to check hemoglobin A1c and a fasting glucose. These are easy to order, and they help us identify prediabetes and diabetes. If they have diabetes, we work with their primary care physician, their endocrinologist, to get it under control.

The study allowed patients up to 3 months on their abiraterone and ADT before starting capivasertib, so you don't need to start all the drugs at once. Start them on the hormonal therapy. You can get their sugars under control and make sure they're managing the abiraterone and prednisone and then add in the capivasertib.

For things like rash and diarrhea, have some over-the-counter steroid cream on hand, so as soon as they get symptoms, they can start that. These are the kinds of management things that can help keep those toxicities from getting into grade 3 toxicities and keep your patients on treatment. We learned a lot of this while doing the study, not before. I think in real-world practice, we can actually do better than what we did in the trials, and maybe even have a higher percentage of patients tolerate this drug long-term.

Urology Times: The approval is for patients with PTEN deficient tumors as identified by a companion diagnostic assay. How do you anticipate PTEN testing being incorporated into routine evaluation for these patients?

George: As you said, testing should be done routinely. If testing is only done on a case-by-case basis, when the treating physician is suspicious of PTEN deficiency, we're going to miss a lot of cases. It's 1 in 4 patients, so anyone with mAPMN/S should be getting PTEN testing. At Duke, because PTEN has important prognostic significance, even in localized disease, we're going to be doing routine PTEN immunohistochemistry testing in patients with any intermediate- or high-risk disease. That eliminates the need for this individualized testing. Whether you use that information or not is going to be up to the clinician. Much of it could be helpful in deciding which patients get radiation therapy, if we want to add hormonal therapy, or in identifying patients appropriate for active surveillance. For our patients with metastatic prostate cancer that is still sensitive to hormonal therapy, we want to identify these patients so we can opt for the addition of capivasertib.

Immunohistochemistry testing is the preferred method. That said, there are a number of labs out there that do both next-generation sequencing as well as immunohistochemistry. Foundation Medicine, Labcorp, Caris, and Tempus all offer that as an option. If you're ordering next-gen sequencing on your patient's tissue, you can also request that. Our in-house pathology lab will be doing it. A lot of community and health system pathology groups are comfortable doing routine immunohistochemistry testing. This drug has already been approved for breast cancer, but it was approved based on genetic sequencing for PI3K loss and AKT mutation, not so much for PTEN loss. This is going to be new, and it is something I think urologists are going to have to ask for, whether it's in conjunction with next-gen sequencing or with their local pathology group. It's not a heavy ask for your pathologist to do this and to make it a routine test.

Urology Times: Looking ahead, what questions remain unanswered? What future studies do you foresee on biomarker-driven treatment selection in prostate cancer?

George: This is an important breakthrough and one more example of precision medicine in prostate cancer. We're using precision medicine in lung cancer, colon cancer, melanoma, and other settings. It's important for urologists now to recognize that this era is here for prostate cancer as well. We have BRCA mutations and HRR alterations now that can be guiding PARP inhibition in the mAPMS space.

There are other treatments that are also getting broader label indications. We already have docetaxel in combination with our androgen receptor pathway inhibitors for patients with high-volume metastatic prostate cancer. Whether these patients should be receiving docetaxel chemotherapy, a PARP inhibitor, or capivasertib is a question we need to address. Is there a sequence to these medicines? Are there certain patients where one approach makes more sense than another? These are all unanswered questions. Other agents like radioligand therapies may get approved in this space and offer another approach in this population. We'll need to know how to navigate that. We'll need a lot more clinical research in this space.

There also may be other pathways associated with PTEN deficiency. You may see other approaches combined with this in the future, or in sequence, that I think could build on these results as well. Now we're in an era where PTEN deficiency matters. It matters for prognosis, treatment, and how we can improve the lives of patients who may have some of the worst prostate cancers out there.

Urology Times: Is there anything else that you’d like to add?

George: It's important for people to realize that when we add on therapy, it's going to be difficult to see the benefits of that therapy. We're going to see the toxicities associated with therapy, but on an individual basis, where we would already see PSAs decline, it's going to be difficult to see the benefits. It's important for people to realize that this has proven benefit. We'll hopefully see more long-term data associated with it, but this biology is different.

One other thing we learned from this trial that is important for urologists to know is that, when patients met the criteria of castration resistance—this is typically an indication for a change in therapy—they met that criteria either by radiographic progression, a symptomatic skeletal event, death, or a [prostate-specific antigen] (PSA) progression. Historically we're used to PSA progression as our indication that the treatment is no longer working. What was interesting in the CAPItello-281 study is that in our control arm, and to a lesser extent in the capivasertib arm, the majority of progressions to castration resistance occurred in patients without a PSA rise. So, if you're following these patients simply by their PSA and you are not doing regular scans, particularly in these first 2 years when the majority of these castration-resistant events are occurring, you're going to miss a number of patients progressing. Death is obviously separate; there were few of those. But for the others, this disease biology may be different and may be driving some of this non-PSA progression because it's an independent pathway. For urologists, I would encourage you, like oncologists, to stay on the scan schedule of every 3 months with these patients, at least for the first 2 years. Even if the PSAs are down, these patients are at risk.

REFERENCES

1. FDA approves capivasertib with abiraterone and prednisone for PTEN-deficient androgen pathway modulation-naïve or -sensitive prostate cancer. News release. US Food & Drug Administration. June 12, 2026. Accessed June 17, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-abiraterone-and-prednisone-pten-deficient-androgen-pathway-modulation

2. Truqap combination approved in the US as first and only targeted treatment for PTEN-deficient metastatic hormone-sensitive prostate cancer. News release. AstraZeneca. June 12, 2026. Accessed June 17, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/truqap-approved-in-us-for-prostate-cancer.html

3. Fizazi K, Clarke NW, Santis MD, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol. 2026;37(1):53-68. doi:10.1016/j.annonc.2025.10.004