Talazoparib plus Enzalutamide after progression to prior ARPi in Metastatic Prostate Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Oncosur

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Male Urogenital Diseases [C12]

Trial duration

5 Jul 2024 → ongoing

Decision date (initial)

2025-08-18

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Fundación OncoSur

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To determine the anti-tumor activity of talazoparib plus enzalutamide as 1L treatment for metastatic castration resistant prostate cancer (mCRPC) in patients whose disease has progressed on ARPi, analyzed separately in the following subgroups:
• Post-abiraterone acetate
• Post-direct AR inhibitors

Secondary objectives 2

1. - To evaluate time to and survival from progression events in patients treated with talazoparib plus enzalutamide compared to enzalutamide alone after progression on prior ARPi, analyzed both separately and jointly in the following subgroups: Post-abiraterone acetate and Post-direct AR inhibitors.
2. To characterize the safety and tolerability of talazoparib plus enzalutamide in this population

Conditions and MedDRA coding

Prostate Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. Male age 18 or older
2. Histological diagnosis of prostate adenocarcinoma without neuroendocrine differentiation or small cell features.
3. 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.
4. ECOG performance status 0 or 1.
5. 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.
6. Willing to provide blood samples for biomarker analysis
7. Willing to give consent to sequencing of DDR genes for analysis of the prevalence of somatic and germline aberrations in DNA damage repair genes.
8. Metastatic (M1) prostate cancer documented by bone scan, or soft tissue disease documented by computed tomography (CT), or magnetic resonance imaging (MRI).
9. Asymptomatic or minimally symptomatic prostate cancer at screening.
10. Estimated life expectancy of ≥ 6 months from screening.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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).
16. Ability to swallow study medication tablets and comply with study requirements
17. 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.
18. Subjects must not donate sperm starting at screening and throughout the study period and for 3 months after the final abiraterone acetate administration.
19. 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.
20. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion criteria 17

1. Prior ARPi treatment for < 12 weeks or disease progression (either PSA or radiographic progression) within 6 months of starting abiraterone or ARi.
2. Known or suspected brain metastasis or active leptomeningeal disease.
3. Symptomatic or impending spinal cord compression or cauda equina syndrome.
4. 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
5. 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.
6. 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.
7. Major surgery within 4 weeks prior to randomization or patients who have not recovered from the side effects of any major surgery.
8. 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.
9. 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.
10. Congenital long QT syndrome or ECG at screening with QT interval corrected using Fridericia’s formula (QTcF)>500 milliseconds.
11. 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
12. 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.
13. Any clinically significant gastrointestinal disorder affecting absorption (i.e., extensive small bowel resection, active inflammatory bowel disease).
14. Active or symptomatic viral hepatitis or chronic liver disease
15. Known/possible hypersensitivity, allergies to enzalutamide, talazoparib or any of capsule excipients.
16. 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.
17. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. PSA response: percentage of patients with PSA decline ≥ 50% from baseline PSA value at 12-16 weeks and/or
2. Objective response rate: percentage of patients with radiographic response (partial or complete) during the first 16 weeks on follow up as per investigator assessment of soft tissue/visceral disease per RECIST 1.1, in subjects with measurable lesions.

Secondary endpoints 4

1. Radiographic progression free survival (rPFS), based on RECIST v1.1 and/or PCGW3 guidelines
2. Time to PSA progression (TTPP), based on PCGW3 guidelines.
3. Time to unequivocal clinical progression (TTCP), based on PCGW3 guidelines
4. Incidence of adverse events (AEs), based on CTCAE v.5.0 criteria

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Oncosur

Sponsor organisation

Fundacion Oncosur

Address

Gran Via Del Marques Del Turia No 65 3 11

City

Valencia

Postcode

46004

Country

Spain

Scientific contact point

Organisation

Fundacion Oncosur

Contact name

Dr Elena Castro

Public contact point

Organisation

Fundacion Oncosur

Contact name

Dr Elena Castro

Third parties 2

Locations

2 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 20 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications