Evaluation of Talazoparib and Enzalutamide Efficacy in Metastatic Castration-Resistant Prostate Cancer Post-Abiraterone Progression
- Trial ID
- 2023-510536-37-00
- Protocol
- TEAM PC
- Sponsor
- Fundacion Oncosur
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the anti-tumor activity of **talazoparib** plus **enzalutamide** as a first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) who have experienced disease progression on **abiraterone**. This is clinically relevant as it aims to provide an effective treatment option for mCRPC patients who have limited therapeutic alternatives after progression on abiraterone, potentially improving patient outcomes and quality of life.
Secondary objectives include:
- Evaluating the time to disease progression, including radiographic, PSA, and clinical progression, in patients treated with talazoparib plus enzalutamide after progression on abiraterone.
- Characterizing the safety and tolerability of talazoparib plus enzalutamide in this patient population.
Participants
The clinical trial focuses on evaluating the **anti-tumor activity** of talazoparib combined with enzalutamide as a first-line treatment for metastatic castration-resistant **prostate cancer** (mCRPC) in patients whose disease has progressed on abiraterone. The study population consists exclusively of male participants aged 18 years and older, with an estimated life expectancy of at least six months from screening. Participants are required to be undergoing ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) agonist or antagonist unless they have undergone bilateral orchiectomy. The trial does not include female subjects and does not involve a vulnerable population. Participants must have a histological diagnosis of prostate adenocarcinoma without neuroendocrine differentiation or small cell features and must be willing to comply with all study requirements, including providing tumor biopsies and blood samples for biomarker analysis. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, phase II study to evaluate the efficacy of combining **talazoparib** and **enzalutamide** as a first-line treatment for patients with metastatic castration-resistant **prostate cancer** (mCRPC) who have shown disease progression following treatment with abiraterone. The trial is expected to commence recruitment in May 2024 and conclude by May 2027. Participants will be randomly assigned to receive either the investigational combination therapy or a comparator, with the primary objective being to assess the anti-tumor activity of the combination therapy.
The trial will involve a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, ongoing androgen deprivation therapy, and disease progression after abiraterone treatment. Participants will be required to have adequate organ function and agree to comply with study requirements, including the provision of tumor biopsies and blood samples for biomarker analysis. Following the screening, participants will undergo regular follow-up visits to monitor treatment response and safety, with assessments including PSA response and objective response rate. The end-of-study visit will occur after the completion of the treatment period, which is set at a maximum of four months.
Participant involvement is expected to last for the duration of the treatment period, with additional follow-up as necessary to assess long-term outcomes. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous scientific and ethical standards, ensuring that all procedures are conducted in accordance with applicable regulations and guidelines.
Treatment
The clinical trial involves the administration of **ENZALUTAMIDE**, a chemical active substance, in the form of soft capsules. The pharmaceutical form is specified as "CAPSULE, SOFT," and the medication is administered orally. The maximum daily dose of enzalutamide is 160 mg, with a total maximum dose of 4480 mg over a treatment period of 4 weeks. The role of enzalutamide in the trial is as a test medication, and it is not a paediatric formulation. The trial does not involve any changes in the marketing authorization status of this product.
**TALAZOPARIB** is another experimental medication used in this trial, provided in two different dosages: Talzenna 0.1 mg and Talzenna 0.25 mg hard capsules. Both formulations are administered orally. The maximum daily dose for talazoparib is 0.5 mg, with a total maximum dose of 14 mg over a 4-week treatment period. The capsules are supplied by Pfizer Europe MA EEIG, and they differ in color from the commercial product. Talazoparib is also a chemical active substance and serves as a test medication in the trial. The pharmaceutical form is "CAPSULE, HARD," and it is not a paediatric formulation.
In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to evaluate the efficacy of the combination of talazoparib and enzalutamide as a first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) following progression on abiraterone. Participant compliance with the dosing schedule will be monitored throughout the trial period.
Efficacy
The efficacy of the combination treatment of **Talazoparib** and **Enzalutamide** in patients with metastatic castration-resistant prostate cancer (mCRPC) will be assessed through several primary and secondary endpoints. The primary endpoints include the percentage of patients achieving a prostate-specific antigen (PSA) response, defined as a decline of ≥50% from baseline PSA value at 12-16 weeks, and the objective response rate, which measures the percentage of patients with a radiographic response (partial or complete) during the first 16 weeks, as per investigator assessment of soft tissue/visceral disease using RECIST 1.1 criteria.
Secondary endpoints will evaluate radiographic progression-free survival (rPFS) based on RECIST v1.1 and/or PCGW3 guidelines, time to PSA progression (TTPP) based on PCGW3 guidelines, and time to unequivocal clinical progression (TTCP) also based on PCGW3 guidelines. Additionally, the incidence of adverse events (AEs) will be monitored according to CTCAE v.5.0 criteria. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to determine the anti-tumor activity of the treatment regimen.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male age 18 or older
- Histological diagnosis of prostate adenocarcinoma without neuroendocrine differentiation or small cell features.
- Willing and able to provide written informed consent to participate in the study. Written consent must be given before registration, according to ICH/GCP, and national/local regulations.
- ECOG performance status 0 or 1.
- Willing to provide tumor biopsies during the study. Note: At study entry, the pre-treatment newly acquired tumor biopsy (fresh-frozen and FFPE material could be replaced by an archived tumor biopsy upon agreement from the study chief investigator if such biopsy has been taken after progression to metastatic castration resistance and has both archived fresh-frozen material and a FFPE block with a minimum tumor content >30%. Still the patient must be amenable and willing to undergo a new mandatory post-treatment biopsy.
- Willing to provide blood samples for biomarker analysis
- Willing to give consent to sequencing of DDR genes for analysis of the prevalence of somatic and germline aberrations in DNA damage repair genes.
- Metastatic (M1) prostate cancer documented by bone scan, or soft tissue disease documented by computed tomography (CT), or magnetic resonance imaging (MRI).
- Asymptomatic or minimally symptomatic prostate cancer at screening.
- Estimated life expectancy of ≥ 6 months from screening.
- Ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone (GnRH) agonist or antagonist for participants who have not undergone bilateral orchiectomy must be in place before screening and must continue throughout the study.
- Disease progression after at least 12 weeks of treatment with a prior androgen-receptor signalling inhibitor (ARPi), including abiraterone acetate or a direct AR inhibitor, such as enzalutamide, apalutamide, or darolutamide, for metastatic hormone-sensitive prostate cancer. Note: Patients who previously received Enzalutamide can be recruited but up to a maximum of 6. Those patients will be included directly into the experimental arm. Progression is defined as: a. PSA rise of ≥ 25% and an absolute increase of ≥ 2 ng/mL above nadir (or baseline for patients with no PSA decline), confirmed by a second PSA value at least 3 weeks later. and / or b. Limited radiographic progression: maximum of 2 new bone metastases, no new soft tissue metastasis and <50% increase in the size of measurable soft tissue lesions.
- Participants who have received prior docetaxel must meet the following criteria: a. Received a maximum of 6 cycles of docetaxel for mHSPC. and b. Received the last dose of docetaxel ≥ 6 months prior to randomization.
- Participants who have received prior Lu177-PSMA must meet the following criteria: a. Received a maximum of 6 cycles of Lu177-PSMA for mHSPC, and b. Received the last dose of Lu177-PSMA ≥ 6 months prior to randomization.
- Adequate organ function within 28 days before the first study treatment on Day 1, defined by the following: a. Haemoglobin ≥10 g/dL, no blood transfusions within 14 days before obtaining the haematology laboratory tests at screening, b. Platelets ≥100,000/μL no platelets transfusions within 14 days before obtaining the haematology laboratory tests at screening, c. Neutrophils ≥1500/μL, no growth factors given within 14 days before obtaining the haematology laboratory tests at screening, d. Serum creatinine <1.5X ULN or calculated creatinine clearance ≥ 50 mL/min e. Albumin > 3 g/dL, f. AST or ALT <2.5 × ULN (<5 × ULN if liver function abnormalities are due to hepatic metastasis). g. Total serum bilirubin <1.5 × ULN (<3 × ULN for participants with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation).
- Ability to swallow study medication tablets and comply with study requirements
- Agrees to use a condom and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant, starting contraception at screening and continue throughout the study period and for 3 months after the final treatment administration, unless the patient is unable to maintain intercourse due to the androgen deprivation.
- Subjects must not donate sperm starting at screening and throughout the study period and for 3 months after the final abiraterone acetate administration.
- Subject agrees not to participate in another interventional study with experimental medical products or anticancer drugs not approved in this setting while on treatment in this study. Exceptions could be allowed for protocols investigating the survival or quality of life impact of common routine or conventional drugs (i.e. AAS, statins, oral antidiabetic drugs) as long as they do not interfere with the study treatment and the evaluation of the main study aims.
- Willing and able to comply with all scheduled visits, treatment plan, laboratory tests and other study procedures.
Exclusion Criteria
- Prior ARPi treatment for < 12 weeks or disease progression (either PSA or radiographic progression) within 6 months of starting abiraterone or ARi.
- Known or suspected brain metastasis or active leptomeningeal disease.
- Symptomatic or impending spinal cord compression or cauda equina syndrome.
- Use of opiate analgesia for pain from prostate cancer with average BPI score ≥ 6 and/or uncontrolled prostate cancer-related pain requiring increasing doses of opiates within 4 weeks prior to randomization
- Prior treatment with more than one ARPi. This will include abiraterone, enzalutamide, apalutamide, or darolutamide, which are treatments with demonstrated PFS and/or OS benefit in mHSPC, as well as any other novel AR or androgen synthesis directed therapy (with the exception on LHRH/GnRH analogues and/or antagonists) Note: Patients who started on one ARPi and switched to another due to toxicity will only be eligible after prior discussion with the study chair, provided that they were on the first ARPi (other than enzalutamide) for a very limited period of time and can document that they were responding—without PSA rise or worsening symptoms—at the moment they were switched to the second ARPi. Inclusion of such cases will require written notification and approval from the study chair or co‑chair.
- Therapeutic radiation therapy within, 14 days (7 days for limited-field palliative radiotherapy) prior to study enrolment, or patients who have not recovered from radiotherapy-related toxicities to grade ≤ 1 according to NCI-CTCAE v.5.0.
- Major surgery within 4 weeks prior to randomization or patients who have not recovered from the side effects of any major surgery.
- Administration of an investigational therapeutic or invasive surgical procedure (not including surgical castration) within 30 days of Cycle 1 Day 1 or currently enrolled in an investigational study.
- History of seizure or any condition that may predispose to seizure (i.e., prior significant brain trauma, brain vascular malformation, etc) or subjects that have had an unexplained loss of consciousness or transient ischemic attacks within 1 year previous to scheduled day 1 of treatment.
- Congenital long QT syndrome or ECG at screening with QT interval corrected using Fridericia’s formula (QTcF)>500 milliseconds.
- Patients with clinically significant cardiovascular disease including but not limited to any of the following: a) Stroke, transient ischemic attack, unstable angina pectoris or documented myocardial infarction within 12 months prior to study entry. b) Symptomatic pericarditis or clinically significant pericardial effusion or myocarditis c) Documented congestive heart failure (NYHA functional classification III-IV) d) Uncontrolled, persistent hypertension defined as systolic blood pressure >170mmHg or diastolic blood pressure >100mmHg. Subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
- Patients with any of the following cardiac conduction abnormalities: a) Ventricular arrhythmias except for benign premature ventricular contractions b) Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication. c) Conduction abnormality requiring a pacemaker. d) Other cardiac arrhythmia not controlled with medication.
- Any clinically significant gastrointestinal disorder affecting absorption (i.e., extensive small bowel resection, active inflammatory bowel disease).
- Active or symptomatic viral hepatitis or chronic liver disease
- Known/possible hypersensitivity, allergies to enzalutamide, talazoparib or any of capsule excipients.
- Other malignancy except: a) Carcinoma in situ or non-melanoma skin cancer. b) A cancer diagnosed and treated ≥ 5 years before randomization with no subsequent evidence of recurrence.
- Any condition or situation which, in the opinion of the investigator, would put the subject at risk, may confound study results, or interfere with the subject’s participation in this study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 May 2024 | 25 |
 Spain | Recruiting | 01 May 2024 | 78 |
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 |
|---|---|---|---|---|---|---|
Talzenna 0.1 mg hard capsules | Test | HARD CAPSULES | ORAL | 0.5 | 4 | PRD11072548 |
ENZALUTAMIDE | Test | — | ORAL | 160 | 4 | SUB77412 |
Talzenna 0.25 mg hard capsules | Test | HARD CAPSULES | ORAL | 0.5 | 4 | PRD7388550 |
ENZALUTAMIDE | Comparator | — | ORAL | 160 | 4 | SUB77412 |