| 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 rPFS, in patients with mCRPC unselected for DDR status.
- To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging rPFS, in patients with mCRPC harboring DDR deficiencies. |
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| E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives:
- To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging OS in patients with mCRPC unselected for DDR status.
- To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging OS in patients with mCRPC harboring DDR deficiencies.
Other Secondary Objectives:
- To evaluate anti-tumor activity in patients with mCRPC unselected for DDR status and in patients with mCRPC 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 cytotoxic chemotherapy;
- Time to initiation of antineoplastic therapy;
- Time to first symptomatic skeletal event;
- PFS on next line therapy (PFS2);
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. At least 18 years of age. For Japan, at least 20 years of age.
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features. If the patient does not have a prior histological diagnosis, a baseline de novo biopsy must be used to confirm the diagnosis and to support biomarker analysis.
3. Asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) (score on BPI-SF Question #3 must be <4).
4. For enrollment into Part 2 only (optional in Part 1): assessment of DDR mutation status by prospective analysis (de novo or archival tissue), or historical analysis (with Sponsor pre-approval), of most recent tumor tissue per FoundationOne testing. (Note: for patients enrolling in Part 1, DDR deficiency testing is optional).
5. For enrollment into Part 2 only (optional for Part 1): 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, 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. Or ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist for patients who have not undergone bilateral orchiectomy must be initiated at least 4 weeks before Day 1 (Part 1) or randomization (Part 2) and must continue throughout the study.
7. Metastatic disease in bone documented on bone scan or in soft tissue documented on CT/MRI scan. Scans obtained as part of standard of care in the 6 weeks (42 days) prior to Day 1 (Part 1) or randomization (Part 2) can be used if they meet study requirements (Table 2). Measurable soft tissue disease is not required. (Adenopathy below the aortic bifurcation alone does not qualify).
8. Progressive disease at study entry in the setting of medical or surgical castration as defined by 1 or more of the following 3 criteria:
- Prostate specific antigen (PSA) progression defined by rising PSA of at least 2 consecutive rises in PSA to be documented over a reference value (measure 1) taken at least 7 days apart. If the third PSA measure is not greater than the second measure, a fourth PSA measure is required to be taken and be greater than the 2nd measure. The 3rd (or the 4th) confirmatory PSA should be taken within 4 weeks prior to randomization. The initial PSA value must be ≥ 1 μg/L.
- Soft tissue disease progression as defined by RECIST 1.1.
- Bone disease progression defined by Prostate Cancer Working Group 3 (PCWG3) with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan.
9. Ongoing bisphosphonate or denosumab use prior to Day 1 (Part 1) or randomization (Part 2) is allowed but not mandatory.
10. Eastern Cooperative Oncology Group (ECOG) performance status ≤1.
11. Life expectancy 12 months as assessed by the investigator.
12. Able to swallow the study treatment and have no known intolerance to study treatments or excipients.
13. 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 4.4.1) 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. 14. Must agree not to donate sperm from the first dose of study treatment to 4 months after the last dose of study treatment.
15. Evidence of a personally signed and dated informed consent document (and molecular prescreening consent if appropriate) indicating that the patient [or a legally acceptable representative/legal guardian] has been informed of all pertinent aspects of the study.
16. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
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| E.4 | Principal exclusion criteria |
Patients with any of the following characteristics/conditions will be excluded:
1. Any prior systemic cancer treatment initiated in the non-metastatic CRPC and mCRPC disease state. (ADT received in the CRPC disease state is NOT exclusionary.)
2. Patients whose only evidence of metastasis is adenopathy below the aortic bifurcation.
3. Prior treatment with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer.
4. Prior treatment with platinum based chemotherapy within 6 months (from the last dose) prior to Day 1 (Part 1) or randomization (Part 2), or any history of disease progression on platinum based therapy within 6 months (from the last dose).
•Prior docetaxel for mCSPC is allowed if more than 4 weeks have elapsed from the last dose of docetaxel.
5. Treatment with cytotoxic chemotherapy which includes but is not limited to doxetaxel, biologic therapy including sipuleucel-T, or radionuclide therapy received in the castration-sensitive prostate cancer is NOT exclusionary if discontinued in the 28 days prior to Day 1 (Part 1) or randomization (Part 2). Hormonal therapy (eg, bicalutamide, nilutamide, flutamide, estrogens, 5 alpha reductase inhibitors are not exclusionary if discontinued prior to randomization for mCSPC.
*Corticosteroid use of >10 mg/day is exclusionary. (The concomitant use of systemic glucocorticoid administration such as "stress dose" glucocorticoid is permitted when clinically indicated for a life threatening medical condition).
6. Treatment with any investigational agent within before Day 1 (Part 1) or randomization (Part 2).
7. Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days prior to Day 1 (Part 1) or randomization (Part 2).
8. Current use of potent P-gp inhibitors within 7 days prior to Day 1 (Part 1) or randomization (Part 2.) 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 5.9.
9. Major surgery (as defined by the investigator) within 2 weeks before Day 1 (Part 1) or randomization (Part 2), or palliative localized radiation therapy within 3 weeks before randomization (Part 2)
10. Clinically significant cardiovascular disease, including any of the following:
- Myocardial infarction or symptomatic cardiac ischemia within 6 months before Day 1 (Part 1) or randomization (Part 2).
- 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, patients can be rescreened after adequate control of blood pressure is achieved.
Please refer to protocol for the full list of exclusion criteria. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) in patients with mCRPC unselected for DDR status.
- rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) in patients with mCRPC harboring DDR deficiencies. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoints:
- OS in patients with mCRPC unselected for DDR status (alpha-protected).
- OS patients with mCRPC harboring DDR deficiencies (alpha-protected).
Other Secondary Endpoints:
- Proportion of patients with measurable soft tissue disease at baseline with an objective response per RECIST 1.1 in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
- Duration of soft tissue response per RECIST 1.1 in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
- Proportion of patients with PSA response ≥50% in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
- Time to PSA progression in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
- Time to initiation of cytotoxic chemotherapy in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
- Time to initiation of antineoplastic therapy in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
- Time to first symptomatic skeletal event in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
- PFS2 based on investigator assessment separately in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
- Time to opiate use for prostate cancer pain in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies.
- Incidence of adverse events characterized by type, severity (graded by NCI CTCAE version 4.03), timing, seriousness and relationship to study treatment.
- PK characterized by pre-dose trough and post-dose plasma concentrations of talazoparib, enzalutamide and its N-desmethyl metabolite.
- PROs in patients with mCRPC unselected for DDR status and in patients with mCRPC harboring DDR deficiencies:
- Change from baseline in patient-reported pain symptoms per BPI-SF;
- Change from baseline in patient-reported general health status per EQ-5D-5L;
- Change from baseline in patient-reported cancer-specific global health status/QoL, functioning, and symptoms per EORTC QLQ-C30;
- Time to deterioration in patient-reported pain symptoms per BPI-SF;
- Time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30;
- Time to definitive deterioration in patient-reported disease-specific urinary symptoms per EORTC QLQ-PR25. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Part 1 and Part 2. Part 2 sequential cohorts |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 116 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| New Zealand |
| Norway |
| Peru |
| Poland |
| Portugal |
| South Africa |
| Spain |
| Sweden |
| United Kingdom |
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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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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