CAPItello-281 shows Truqap plus Zytiga extends rPFS in PTEN-deficient mHSPC with manageable toxicity and preserved overall quality of life.
The addition of Zytiga (abiraterone) to Truqap (capivasertib) significantly prolonged radiographic progression-free survival (rPFS) in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer without meaningfully compromising functional well-being or overall quality of life, according to data from the phase 3 CAPItello-281 trial.
In a presentation of the data at the
CAPItello-281 met its primary end point, demonstrating a statistically significant improvement in rPFS with Truqap plus Zytiga (507 patients) versus placebo plus Zytiga (505 patients). Patients treated with Truqap plus Zytiga achieved a median rPFS of 33.2 months compared with 25.7 months in those treated with placebo plus Zytiga (HR, 0.81).
“Capivasertib in combination with abiraterone represents a potential first-in-class targeted treatment for patients with PTEN-deficient mHSPC,” George, director of Genitourinary Oncology at Duke Cancer Institute and professor of medicine and surgery at Duke University School of Medicine, explained.
How the CAPItello-281 trial was designed
CAPItello-281 is a large, global, randomized study enrolling patients with metastatic hormone-sensitive prostate cancer whose tumors demonstrated PTEN loss in at least 90% of cells by immunohistochemistry. In total, 1,012 patients were randomized 1:1 to receive Truqap plus Zytiga and prednisone or placebo plus Zytiga and prednisone, all on a backbone of androgen deprivation therapy.
PTEN-deficient: Tumors with low or missing PTEN, a gene that normally slows cancer growth.
Radiographic progression-free survival (rPFS): How long a patient lives without cancer growing on scans.
Androgen deprivation therapy (ADT): Hormone therapy that lowers testosterone to slow prostate cancer.
Patient-reported outcomes: Questionnaires about how patients feel and function during treatment.
Truqap or placebo was administered at 400 mg twice daily on an intermittent schedule of 4 days on and 3 days off, along with 1000 mg once a day plus androgen deprivation therapy. According to George, this dosing strategy was selected to maintain efficacy but allow for mitigation of cumulative side effects.
The primary end point was investigator-assessed rPFS, with overall survival as a key secondary end point. Patient-reported outcomes and tolerability were prespecified exploratory analyses.
Exploring the patient-reported outcomes
Patient-reported outcomes were assessed using the Functional Assessment of Cancer Therapy–Prostate questionnaire. Compliance exceeded 80%.
Findings showed that for Functional Assessment of Cancer Therapy–Prostate physical well-being, the mean change from baseline across all time points was −1.7 with Truqap plus Zytiga (309 patients) versus −1.3 with placebo plus Zytiga (317 patients), which did not meet the prespecified threshold for a clinically meaningful three-point change.
Regarding time to clinically meaningful deterioration in physical well-being, events occurred in 175 patients in the Truqap arm and 152 patients in the placebo arm, with median times of 7.2 months and 14.6 months, respectively (HR, 1.43).
For Functional Assessment of Cancer Therapy–Prostate functional well-being, the mean change from baseline across all time points was −1 with Truqap plus Zytiga (309 patients) versus −0.7 with placebo plus Zytiga (317 patients), which did not meet the prespecified three-point threshold for clinical meaningfulness.
Functional well-being, which reflects daily activities, work, sleep and enjoyment of life, did not differ meaningfully between treatment arms. Total Functional Assessment of Cancer Therapy–Prostate scores were comparable between groups, indicating that overall quality of life was maintained despite higher toxicity rates in the experimental arm.
What was observed regarding safety and tolerability?
Overall side effect rates, grade 3 or higher side effects and serious side effects were higher in the Truqap arm (98.8%; 67%; and 42.5%) compared with the placebo arm (92%; 40.4%; 26%). Discontinuation due to side effects occurred in approximately 18% of patients receiving Truqap compared with 4.8% of patients receiving placebo.
The most common side effects were consistent with AKT inhibition and included diarrhea (51.9%), hyperglycemia (38%) and rash (35.4%). Median time to onset was approximately 12 to 13 days for rash and diarrhea and within 2 months for hyperglycemia.
Management strategies relied largely on supportive care. Rash was treated with antihistamines and topical steroids, diarrhea with loperamide and hyperglycemia primarily with metformin rather than insulin. Dose interruptions and reductions were more common for rash, and permanent discontinuation was uncommon for diarrhea or hyperglycemia.
“The common side effects are AKT inhibition–related on-target effects that occur early and are manageable,” George concluded. “Despite this, our patient-reported outcomes suggest that the functional aspects and overall quality of life are not affected.”
Additional findings from CAPItello-281
Additional analyses examined outcomes across higher thresholds of PTEN loss. In the Truqap arm, rPFS was consistent regardless of the degree of PTEN loss. In the control arm, higher levels of PTEN loss were associated with worse outcomes.
Among patients with at least 95% PTEN loss, treatment with Truqap plus Zytiga (404 patients) resulted in a median rPFS of 33.2 months compared with 22.7 months for those treated with placebo plus Zytiga (410 patients; HR, 0.75). In patients with at least 99% PTEN loss, the median rPFS was 34.1 months with Truqap plus Zytiga (205 patients) versus 22.4 months with placebo plus Zytiga (196 patients; HR, 0.71).
Among patients with complete PTEN loss, Truqap plus Zytiga (169 patients) achieved a median rPFS of 34.1 months compared with 22.1 months for placebo plus Zytiga (162 patients; HR, 0.68).
George highlighted the discordance between prostate-specific antigen changes and radiographic progression in this population, noting that the majority of patients develop radiographic progression without a prostate-specific antigen rise.
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