Efficacy and Safety of Capivasertib Plus Abiraterone in PTEN-Deficient Metastatic Hormone-Sensitive Prostate Cancer: A Phase III Randomized, Double-Blind, Placebo-Controlled Trial
- Trial ID
- 2023-504998-20-00
- Protocol
- D361BC00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the effect of **capivasertib** combined with **abiraterone** versus placebo combined with abiraterone on radiographic progression-free survival (rPFS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) characterized by PTEN deficiency. This objective is clinically relevant as it aims to determine the efficacy of the treatment in delaying disease progression, which is crucial for improving patient outcomes in this specific cancer subtype.
Secondary objectives include: - Comparing the effect of capivasertib and abiraterone versus placebo and abiraterone on overall survival. - Assessing the time to start of first subsequent therapy or death (TFST). - Evaluating time to symptomatic skeletal event-free survival (SSE-FS). - Measuring time to pain progression (TTPP). - Determining time to PSA progression. - Assessing progression-free survival after next-line treatment (PFS2). - Evaluating the pharmacokinetics (PK) of capivasertib in combination with abiraterone.
Participants
The clinical trial involves a total of **741 male participants** diagnosed with **metastatic hormone-sensitive prostate cancer** characterized by PTEN deficiency. The study population comprises adult males, with age categories ranging from middle-aged to elderly. Participants were selected based on specific inclusion criteria, including histologically-confirmed de novo metastatic hormone-sensitive prostate adenocarcinoma, a valid PTEN IHC result indicating PTEN deficiency, and ongoing androgen deprivation therapy (ADT). The trial excludes female subjects and does not involve a vulnerable population. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are asymptomatic or mildly symptomatic with no significant deterioration in health status over the previous two weeks. Lifestyle considerations include the ability to swallow and retain oral medication, and adherence to contraceptive measures or abstinence. The trial does not specify any particular dietary or physical activity requirements for participants.
Plans and Procedures
The clinical trial is a **Phase III**, double-blind, randomized, placebo-controlled study designed to evaluate the efficacy and safety of **capivasertib** in combination with **abiraterone** compared to placebo plus abiraterone in patients with **metastatic hormone-sensitive prostate cancer** characterized by PTEN deficiency. The primary objective is to assess radiographic progression-free survival (rPFS) as determined by the investigator. Secondary endpoints include overall survival, time to start of first subsequent therapy or death, time to symptomatic skeletal event-free survival, time to pain progression, pharmacokinetics of capivasertib, and safety and tolerability assessments.
The trial is expected to commence recruitment on May 3, 2024, and conclude by March 26, 2027. Participants will be randomly assigned to receive either the investigational treatment or placebo, with both groups receiving abiraterone. The study will involve multiple visits, starting with a screening visit to confirm eligibility based on criteria such as histologically confirmed metastatic hormone-sensitive prostate adenocarcinoma, PTEN deficiency, and ongoing androgen deprivation therapy. Participants must also have a performance status of 0 to 1 and a minimum life expectancy of 12 weeks.
Following the screening, participants will undergo regular follow-up visits to monitor treatment effects and safety, with assessments including imaging studies to evaluate disease progression. The end-of-study visit will occur upon completion of the treatment period or earlier if specific conditions necessitate withdrawal, such as significant adverse events or disease progression. The expected duration of participant involvement is contingent on individual response and tolerance to the treatment, with early termination possible under predefined circumstances.
Treatment
The clinical trial involves the administration of **Capivasertib**, a film-coated tablet for oral use. Capivasertib is a chemical compound with the active substance name **CAPIVASERTIB**. The pharmaceutical form is a film-coated tablet, and it is manufactured by AstraZeneca AB. The administration route is oral, and the dosing schedule is determined by the study protocol, with a maximum treatment period of 99999 days. The trial does not specify a maximum daily or total dose amount, indicating that dosing will be adjusted based on individual patient needs and study requirements. Participant compliance will be monitored through regular assessments and adherence checks.
**Abiraterone Acetate** is also used in this study as a film-coated tablet for oral administration. The active substance is **ABIRATERONE ACETATE**, and it is also produced by AstraZeneca AB. Similar to Capivasertib, the dosing schedule and administration are guided by the study protocol, with a maximum treatment period of 99999 days. The trial does not specify a maximum daily or total dose amount, allowing for flexibility in dosing as per clinical judgment and patient response. Compliance with the medication regimen will be monitored throughout the study duration.
The study includes a **Placebo** for Capivasertib, which is a film-coated tablet designed for oral use. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment the participants are receiving. The placebo administration follows the same route and frequency as the active Capivasertib tablets, with compliance monitoring in place to ensure adherence to the study protocol.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is **Radiographic Progression-free Survival (rPFS)** in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer (mHSPC). This will be assessed using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) for soft tissue and the Prostate Cancer Working Group 3 (PCWG3) criteria for bone, as evaluated by the investigator.
Secondary endpoints include the comparison of overall survival, time to start of first subsequent therapy or death (TFST), time to start symptomatic skeletal event-free survival (SSE-FS), and time to pain progression (TTPP) between the treatment groups. Additionally, the pharmacokinetics (PK) of capivasertib in combination with abiraterone will be evaluated, along with the safety and tolerability of capivasertib plus abiraterone compared to placebo plus abiraterone in patients with PTEN-deficient mHSPC.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Asymptomatic or mildly symptomatic, histologically-confirmed de novo metastatic hormone-sensitive prostate adenocarcinoma without small cell tumours 2. Consent to provide a FFPE tissue block (preferred) or slides. Tissue from bone metastases is not acceptable 3. A valid PTEN IHC result indicating PTEN deficiency (centralized testing) 4. Metastatic disease documented prior to randomisation by clear evidence of ≥ 1 bone lesion and/or ≥ 1 soft tissue lesion accurately assessed at baseline and suitable for repeated assessment with CT and/or MRI. PSMA PET identification only will not be eligible 5. Candidate for abiraterone and steroid therapy 6. Ongoing ADT with GnRH analogue, or LHRH agonists or antagonist, or bilateral orchiectomy 7. Eastern Cooperative Oncology Group (ECOG)/WHO performance status 0 to 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks 8. Able and willing to swallow and retain oral medication 9. 7 day Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory(BFI) questionnaires and the analgesic diary during screening completed 10. Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
Exclusion Criteria
- 1.Prior radical prostatectomy or definitive radiotherapy (RT) with therapeutic intent for prostate cancer. Palliative RT is allowed within 4 wks before start of study 2.Major surgery within 4 wks of start of study 3.Brain metastases, or spinal cord compression (unless asymptomatic, treated and stable 4 Past medical history or evidence of ongoing interstitial lung disease or radiation pneumonitis requiring steroids 5.Any of the following cardiac criteria: -Mean resting QTc >470 msec -History of QT prolongation associated with other medications that required discontinuation - Family history of long QT syndrome or unexplained sudden death under the age of 40 - Medical history significant for arrhythmia, symptomatic or requiring treatment; symptomatic or uncontrolled atrial fibrillation; or asymptomatic sustained ventricular tachycardia - Any clinically important abnormalities of resting ECG - Factors that increase the risk of QTc prolongation or of arrhythmic events, or any concomitant medication known to significantly prolong the QT interval and associated with Torsade de Pointes - Experience of any of the following in the preceding 3 months: coronary artery bypass graft, angioplasty, myocardial infarction or unstable angina pectoris - Congestive heart failure NYHA Grade ≥2 - Symptomatic hypotension (SBP<90 mmHg and/or DBP<50mmHg)or uncontrolled hypertension (SBP ≥160 mmHg or DBP ≥95 mmHg) 6. Any of following clinically significant abnormalities of glucose metabolism: - Patients with diabetes mellitus type 1 or 2 requiring insulin - HbA1c ≥8.0% (63.9 mmol/mol) 7. Inadequate bone marrow reserve or organ function: - Neutrophils <1.5x109/L - Platelets <100x109/L - Hb <9g/dL (<5.59 mmol/L) - ALT and AST >2.5x ULN if no liver metastases or >5x ULN if liver metastases - Bilirubin >1.5x ULN - CrCL <50 mL/min 8. Severe or uncontrolled systemic diseases, including active bleeding diatheses, active infection including hepatitis B and C. diagnosis with HIV or a history of an AIDS opportunistic infection within the past 12 months 9. Unevaluable for both bone and soft tissue progression as defined by the following : bone "superscan" and no soft tissue lesion evaluable by RECIST 10.Conditions that would preclude adequate absorption of capivasertib
- Any other clinical finding that, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug 12. Evidence of dementia, altered mental status, or any psychiatric condition prohibiting understanding or rendering of informed consent 13. Previous allogeneic bone marrow or solid organ transplant 14. History of another primary malignancy except for malignancy treated with curative intent with no known disease ≥ 2 years before starting study and of low recurrence risk 15. Following treatments: - Nitrosourea or mitomycin C within 6 wks of the start of study - Any other anticancer therapy or immunosuppressant medication (other than corticosteroids) within 3 wks of the start of study - Strong inhibitors or inducers of CYP3A4 within 2 wks before the start of study - Drugs known to prolong the QT interval and associated with torsades de pointes within 5 T½of the start of the study 16. Participation in another clinical study with an investigational product administered in the last 30 days or 5 half-lives whichever is longer 17. History of hypersensitivity to active or inactive excipients of capivasertib, abiraterone, or drugs with a similar chemical structure or class 18. Involvement in the planning and/or conduct of the study 19. Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study requirements 20. Any restriction or contraindication based on the local prescribing information that would prohibit the use of abiraterone
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 03 May 2024 | 20 |
 Bulgaria | Not Recruiting | 03 May 2024 | 21 |
 Czechia | Not Recruiting | 03 May 2024 | 13 |
 France | Not Recruiting | 03 May 2024 | 38 |
 Germany | Not Recruiting | 03 May 2024 | 22 |
 The Netherlands | Not Recruiting | 03 May 2024 | — |
 Poland | Not Recruiting | 03 May 2024 | 38 |
 Slovakia | Not Recruiting | 03 May 2024 | 23 |
 Spain | Not Recruiting | 03 May 2024 | 69 |
| Netherlands | — | — | 27 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Capivasertib | Test | FILM-COATED TABLET | ORAL | 0 | 99999 | PRD10312011 |
Capivasertib | Test | FILM-COATED TABLET | ORAL | 0 | 99999 | PRD10312009 |
Placebo for capivasertib film-coated tablet for oral use | Placebo | N/A | — | — | — | N/A |
ABIRATERONE ACETATE | Test | — | ORAL | 0 | 99999 | SUB31647 |