| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castration-resistant Prostate Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Castration-resistant Prostate Cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| •To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging investigator-assessed rPFS, in participants with mCSPC harboring DDR deficiencies. |
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| E.2.2 | Secondary objectives of the trial |
Key Secondary Objective
•To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging OS in participants with mCSPC harboring DDR deficiencies.
Other Secondary Objectives
•To evaluate antitumor activity in participants with mCSPC harboring DDR deficiencies with respect to the following:
•Objective response in measurable soft tissue disease;
•Duration of response in measurable soft tissue disease;
•PSA response;
•Time to PSA progression;
•Time to initiation of antineoplastic therapy;
•Time to first symptomatic skeletal event;
•Opiate use for prostate cancer pain.
•To evaluate safety of talazoparib and enzalutamide administered in combination.
•To evaluate the PK of talazoparib and enzalutamide (and its N desmethyl metabolite) when dosed in combination.
•To evaluate the following participant reported outcomes in each treatment arm in participants with mCSPC harboring DDR deficiencies:
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1.Male participants at least 18 years of age at screening. Refer to Appendix 4 of the protocol for reproductive criteria for male participants.
Type of Participant and Disease Characteristics:
2.Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features. If the participant does not have a prior histological diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis and may also be used to support biomarker analysis.
3.Confirmation of DDR gene mutation status by prospective or historical analysis (with sponsor pre-approval) of blood (liquid biopsy) and/or de novo or archival tumor tissue using FoundationOne Liquid CDx or FoundationOne CDx.
4.Willing to provide tumor tissue when available (de novo or archived) for retrospective molecular profiling analysis, if not already provided as part of inclusion criterion 3.
5.Unless prohibited by local regulations or ethics committee decision, consent to a saliva sample collection for retrospective sequencing of the same DDR genes tested on tumor tissue and blood (liquid biopsy), or a subset thereof, and to serve as a germline control in identifying tumor mutations.
6.Surgically or medically castrated, with serum testosterone ≤50 ng/dL (≤1.73 nmol/L) at screening. Ongoing ADT with a GnRH agonist or antagonist for participants who have not undergone bilateral orchiectomy must be initiated at least 4 weeks before randomization and must continue throughout the study.
7.Metastatic prostate cancer documented by positive bone scan (for bone disease) or metastatic lesions on CT or MRI scan (for soft tissue). Participants whose disease spread is limited to regional pelvic lymph nodes are not eligible. Note: a finding of superscan at baseline is exclusionary.
Allowed Prior Treatments:
8.Prior docetaxel therapy for mCSPC (up to 6 cycles) is allowed (must be completed 2 weeks prior to randomization and all toxicities from treatment have resolved).
9.Treatment with estrogens, cyproterone acetate, or first-generation anti-androgens is allowed until randomization.
10.Other prior therapy allowed for mCSPC; ≤6 months of ADT and ≤3 months of approved NHT in mCSPC (ie, abiraterone + prednisone, apalutamide, or enzalutamide), if required prior to randomization.
11.Participant may have received palliative radiation or surgery for symptomatic control secondary to prostate cancer, which should have been completed at least 2 weeks prior to randomization.
12.ECOG performance status 0 or 1 (see Appendix 11 of the protocol).
13.Adequate organ function within 28 days before the first study treatment on Cycle 1 Day 1, defined by the following:
•ANC ≥1500/µL, platelets ≥100,000/µL, or hemoglobin ≥9 g/dL (may not have received growth factors or blood transfusions within 14 days before obtaining the hematology laboratory tests at screening).
•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).
•AST or ALT <2.5 × ULN (<5 × ULN if liver function abnormalities are due to hepatic metastasis).
•Albumin >2.8 g/dL.
•eGFR ≥30 mL/min/1.73 m2 by the MDRD equation, see Appendix 10 of the protocol).
14.Sexually active participants that in the opinion of the investigator are capable of ejaculating, must agree to use a condom when having sex with a partner (female or male) from the time of the first dose of study treatment through 4 months after last dose of study treatment. Must also agree for female partner of childbearing potential to use an additional highly effective form of contraception (Section 5.3) from the time of the first dose of study treatment through 4 months after last dose of study treatment when having sex with a non pregnant female partner of childbearing potential.
15.Must agree not to donate sperm from the first dose of study treatment to 4 months after the last dose of study treatment.
16.Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
Informed Consent:
17.Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.
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| E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1.Other acute or chronic medical (concurrent disease, infection or co-morbidity) or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that interferes with a participant’s ability to participate in the study, may increase the risk of associated with study participation or study treatment administration, or may interfere with the interpretation of study results, and, in the investigator’s judgment, make the participant inappropriate for entry into the study.
2.History of seizure or any condition (as assessed by investigator) that may predispose to seizure (eg, prior cortical stroke, significant brain trauma), including any history of loss of consciousness or transient ischemic attack within 12 months of randomization.
3.Major surgery (as defined by the investigator) within 2 weeks before randomization.
4.Known or suspected brain metastasis or active leptomeningeal disease.
5.Symptomatic or impending spinal cord compression or cauda equina syndrome.
6.Any history of MDS, AML, or prior malignancy except for the following:
•Carcinoma in situ or non-melanoma skin cancer.
•A cancer diagnosed and treated ≥3 years before randomization with no subsequent evidence of recurrence.
•American Joint Committee on Cancer Stage 0 or Stage 1 cancer <3 years before randomization that has a remote probability of recurrence in the opinion of the investigator and the sponsor.
7.In the opinion of the investigator, any clinically significant gastrointestinal disorder affecting absorption.
8.Clinically significant cardiovascular disease, including any of the following:
•Myocardial infarction or symptomatic cardiac ischemia within 6 months before randomization.
•Congestive heart failure New York Heart Association class III or IV.
•History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsade de pointes) within 1 year before screening.
•History of Mobitz II second degree or third-degree heart block unless a permanent pacemaker is in place.
•Hypotension as indicated by systolic blood pressure <86 mm Hg at screening.
•Bradycardia as indicated by a heart rate of <45 beats per minute on the screening electrocardiogram.
•Uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg or diastolic blood pressure >105 mm Hg at screening. However, participants can be rescreened after adequate control of blood pressure is achieved.
9.Active COVID-19 infection detected by viral test or based on clinical diagnosis (as assessed by investigator). Asymptomatic participants with no active COVID-19 infection detected but positive antibody tests, indicating past infection are allowed.
Prior/Concomitant Therapy:
10.Prior ADT in the adjuvant/neoadjuvant setting, where the completion of ADT was less than 12 months prior to randomization and the total duration of ADT exceeded 36 months.
11.Participant received treatment with systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone within 4 weeks prior to randomization, intended for the treatment of prostate cancer.
12.Any previous treatment with DNA-damaging cytotoxic chemotherapy (ie, platinum based therapy) within 5 years prior to randomization, except for indications other than prostate cancer.
13.Prior treatment with a PARPi.
14.Prior treatment in any setting with NHT, except as described in Inclusion Criterion #10.
15.Current use of potent P-gp inhibitors within 7 days prior to randomization. For a list of potent P-gp inhibitors, and other medications which are exclusionary because of interaction with either talazoparib or enzalutamide, refer to Section 6.5.
Prior/Concurrent Clinical Study Experience:
16.Treatment with any investigational study intervention within 4 weeks before randomization. Exception: COVID-19 vaccines authorized under an emergency use authorization (or equivalent) can be administered without a washout period.
Further exclusion criteria are detailed in the protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| •Investigator-assessed rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) in participants with mCSPC harboring DDR deficiencies. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Radiographic imaging is every 8 weeks through Week 57, (9, 17, 25, 33, 41, 49, 57) then every 12 weeks thereafter until study intervention is discontinued for radiographic progression. |
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| E.5.2 | Secondary end point(s) |
•OS in participants with mCSPC harboring DDR deficiencies (alpha protected).
•Proportion of participants with measurable soft tissue disease at baseline with an objective response per RECIST 1.1.
•Duration of soft tissue response per RECIST 1.1.
•Proportion of participants with PSA response 50% in participants with detectable PSA values at baseline..
•Time to PSA progression.
•Time to initiation of antineoplastic therapy.
•Time to first symptomatic skeletal event.
•Time to opiate use for prostate cancer pain.
•Incidence of AEs characterized by type, severity (graded by NCI CTCAE version 4.03), timing, seriousness and relationship to study intervention.
•Predose trough plasma concentrations of talazoparib, enzalutamide and its N-desmethyl metabolite
•Change from baseline in participant-reported pain symptoms per BPI-SF;
•Change from baseline in participant-reported general health status per EQ-5D-5L;
•Change from baseline in participant-reported cancer specific global health status/QoL, functioning, and symptoms per EORTC QLQ-C30;
•Time to deterioration in participant-reported pain symptoms per BPI-SF;
•Time to definitive deterioration in participant-reported global health status/QoL per EORTC QLQ-C30;
•Time to definitive deterioration in participant-reported disease specific urinary symptoms per EORTC QLQ-PR25.
•Change from baseline in PGI-S.
•ctDNA burden at baseline and on study, as assessed using FoundationOne liquid or another suitable validated assay.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As per protocol , through the treatment period and long term follow up. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| China |
| India |
| Japan |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Russian Federation |
| South Africa |
| Turkey |
| Ukraine |
| United States |
| Belgium |
| Bulgaria |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Slovakia |
| Spain |
| Sweden |
| United Kingdom |
| Czechia |
| Argentina |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 9 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 9 |
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