Today I'm excited to discuss the recently published CAPItello-281 Phase III Study looking at capivasertib with abiraterone in PTEN-deficient hormone-sensitive metastatic prostate cancer. This study was recently published in the annals of oncology led by Dr. Karim Fizazi.
So what is a PTEN-deficiency? Why does it matter? So loss of PTEN leads to activation of the PI3K/AKT pathway. As we see here in our schematic, it leads to loss of regulation of cell growth, survival, and metabolism. Importantly, it leads to an alternative proliferative drive, which is independent of androgen receptor signaling. We know across the spectrum of prostate cancer that loss of this PTEN is associated with advanced stage disease, shorter time to disease progression, and importantly reduced benefit from current standard of care treatments.
So what is capivasertib? It is a potent selective inhibitor of all three AKT isoforms, so AKT1 through three. As we see here again in the schematic, it binds to AKT and it inhibits phosphorylation of downstream substrates. This agent is FDA approved in combination with fulvestrant in patients with hormone receptor-positive, HER2-negative advanced breast cancer.
What is the rationale for combining capi with an androgen receptor blocker? So preclinical PTEN null or deficient prostate tumor models have shown that when you combine these two different agents with alternate mechanisms of action, it leads to an improved inhibition of tumor growth versus just blocking androgen receptors alone. Importantly, capi and abi target independent pathways of tumorigenesis and there is suggestion of a crosstalk between the two pathways, meaning the androgen receptor dependent and the PI3K/AKT pathways, and so potentially a synergistic mechanism of action.
There is a precedent for evaluating an AKT inhibitor with abiraterone. We saw that in the IPATential150 trial that showed an improved efficacy with capivasertib plus abi versus abi alone in PTEN-deficient tumors. So based on that, the study investigators in combination with AstraZeneca designed this global phase-three trial, the CAPItello-281 that was meant to evaluate the efficacy and safety of capi plus abiraterone with prednisone versus placebo plus abi, prednisone in these PTEN-deficient metastatic hormone-sensitive prostate cancer patients.
The eligibility criteria are as follows. So importantly, it was de novo metastatic hormone-sensitive prostate cancer and patients were required based on histology to have PTEN deficiency. The status of this using histology was determined using an investigational antibody for PTEN, which is SP218 that was developed by Roche Diagnostics here locally for us in Tucson, Arizona.
Based on the staining, the pathologist assigned a percentage score from zero to 100 of viable malignant cells with no cytoplasmic staining. If at least 90% of the cells had no staining, meaning at least 90% were PTEN-deficient, then patients were deemed to be study eligible based on that. Importantly, prior therapy in the form of ADT plus or minus abi up to 93 days allowed, but no other prior therapy, be it an alternate ARPI or a chemotherapy, none of that was allowed prior to this trial enrollment.
Here we see the study design of CAPItello-281 as recently presented. The most important takeaway here I want to highlight is that of the 6,200 patients that were evaluated or considered for this trial, it was very easy to get a valid immunohistochemistry result. So logistically very doable, 97%. Importantly, of these 97%, 25% of the patients were PTEN-deficient. So of all-comer, de novo mHSPC patients, we can estimate that about a quarter of them will have a PTEN deficiency.
So it really shows you that this is not an insignificant number. Eventually 1,012 patients were randomized in a one-to-one fashion. The intervention arm, as we mentioned, included capivasertib, which was given at a dose of 400 milligrams twice daily. So it's given four days on, three days off. Then abi is the usual dose of a thousand milligrams, once daily with ADT versus the control arm that was placebo plus the abi.
In terms of study endpoints, the primary endpoint was investigator assessed radiographic progression-free survival. Secondary endpoints were your usual combination of overall survival, time to first subsequent therapy, skeletal event-free survival, pain progression, castration resistance, and PSA progression. Importantly, the investigators also looked at these outcomes in a exploratory post-hoc fashion depending on the degree of PTEN deficiency. So every one of them had 90% or higher, but 90 is different than 95 or 99. So the authors also investigated to see if there was improved benefit in these patients. At this point, I'll turn it over to Zach who'll guide us with the results of this trial.
Zachary Klaassen: Thanks so much, Rashid. Great outline as always. Let's look at the baseline characteristics for these patients. So roughly 500 patients in each arm, median age of 67. About half of these patients were white. This was a global study, so around one-third of patients were Asian and about 1.2% were Black or African American. Even in this population of a poor prognosis, mHSPC patient population, two-thirds of these patients were ECOG-0.
When we look at sites of metastases, majority over 91% were bone metastases. 42% were non-regional lymph nodes. We jumped down to the Gleason score. Almost 80% of these were Gleason eight or higher. 61 to 65% were a high-risk disease. We look at the metastatic volume of disease, nearly three-quarters were high-volume metastatic disease.
This is the primary outcome for CAPItello-281 radiographic progression-free survival, capi plus abi in green, placebo plus abi in purple. We see a median rPFS of 33.2 months in capi plus abi versus 25.7 months in placebo plus abi. Hazard ratio, 0.81, 95% confidence interval, 0.66 to 0.98, and this was a positive trial based on this result.
What's interesting is when we look at rPFS by PTEN deficiency. So Rashid nicely laid out the 90% PTEN deficiency was required to get into the trial. When we look at the patients at a complete PTEN deficiency, 100% we see that the capi plus abi arm had a median rPFS of 34.1 compared to 22.1 months in the placebo plus abi arm. Hazard ratio of 0.68. Again, this was statistically significant.
What's important here is we see a bit of a gradient with more PTEN deficiency. So in the all randomized patients, we see this hazard ratio of 0.81 and we see that the capi plus abi arm basically performs almost exactly the same regardless of the PTEN score, but we see a worsening in the placebo plus abi arm. So this results in a hazard ratio that slightly improves with increasing PTEN deficiency. Overall survival is still immature and we see here not reached in both arms. Hazard ratio 0.9, 95% confidence interval, 0.71 to 1.15.
Several key secondary efficacy analysis. So let's start at the top left. Time to further systemic therapy. This was a numerical benefit for capi plus abi with a hazard ratio of 0.91, not statistically significant. Moving to the right, symptomatic skeletal event-free survival, again, numerically benefiting the capi plus abi arm. Hazard ratio of 0.82, 95% confidence interval, 0.66 to 1.02.
What's important here is time to castration resistance. This was numerically benefiting capi plus abi, but also had a hazard ratio of 0.77 and 95% confidence interval, 0.63 to 0.94. So this is important to patients. This is the time to when their treatment is no longer responding and we see a benefit here favoring the capi plus abi arm. Time to PSA progression, again, we see no difference between the two arms. Hazard ratio, 0.73, 95% confidence intervals crossing one.
In terms of most common treatment adverse events, no surprise that almost all patients had an all grade treatment emergent adverse event. Grade 3+ in the capi plus abi arm, 67% versus 40.4% in the placebo plus abi arm. The three at the top here are the main ones related to capi. This was diarrhea, about 50% all grade, 6.2% Grade 3+. Hyperglycemia, 30% all grade, 10.3% Grade 3+. Rash, 35.4% all grade and 12.3% Grade 3+ in that capi plus abi arm.
So by way of discussion, CAPItello-281 showed a 7.5 month radiographic progression-free benefit with capi plus abi versus placebo plus abi in mHSPC patients. This is the first trial to validate the PI3K/AKT pathway as clinically relevant and an actionable targeted in the metastatic hormone-sensitive prostate cancer population. We know that PTEN-deficient tumors have poor outcomes and this certainly is a population with a high unmet need.
What's important as well as we just discussed is the numerical benefits observed for capi plus abi in clinically relevant and meaningful endpoints such as time to castration resistance, time to PSA progression, and symptomatic skeletal event-free survival. This represents a real benefit for patients by prolonging hormone sensitivity and delaying their need for subsequent treatment.
The 90% loss of PTEN protein by IHC cutoff for defining PTEN deficiency was chosen based on previous phase-three data. We saw previously in the slides that there was a clear trend and worsening prognosis in that control arm and improved treatment effect for the addition of capi to abi with increasing PTEN cutoffs.
I think what's important, and if we go think back to that treatment emergent adverse event slide, discontinuations of capi due to adverse events were early in the treatment process indicating that capi associated adverse events are identified early, specifically the rash, hyperglycemia, and diarrhea.
So by way of take-home and CAPItello-281 the addition of capi to abiraterone plus ADT demonstrated a significant improvement in radiographic progression-free survival versus placebo plus abi in PTEN-deficient mHSPC. This was associated with consistent additional oncologic endpoints and a manageable safety profile.
Finally, these results support combined AKT and AR inhibition with capivasertib plus abiraterone as a targeted approach in PTEN-deficient mHSPC. Thank you so much for your attention and hope you enjoyed this UroToday Journal Club discussion of the CAPItello-281 trial.