Talapro 2: a Phase 3, Randomized, Double Blind, Placebo-Controlled Study of Talazoparib with Enzalutamide in Metastatic Castration Resistant Prostate Cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Apr 2019 → ongoing

Decision date (initial)

2024-10-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2023-509087-20-00

EudraCT number

2017-003295-31

ClinicalTrials.gov

NCT03395197

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacogenomic, Safety, Pharmacodynamic, Pharmacokinetic, Efficacy, Therapy, Pharmacoeconomic

"*Part 1: To determine the starting dose of talazoparib when given in combination with enzalutamide during Part 2 (double blind treatment period).

*Part 2: • To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging BICR assessed rPFS, in participants with mCRPC unselected for DDR status.
• To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging BICR assessed rPFS, in participants with mCRPC harboring DDR deficiencies. "

Secondary objectives 3

1. *Part 1: • To characterize the steady state PK of talazoparib and enzalutamide and its N desmethyl metabolite when given in combination.
2. *Part 2: • To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging OS in participants with mCRPC unselected for DDR status.
3. *Part 2: • To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging OS in participants with mCRPC harboring DDR deficiencies.

Conditions and MedDRA coding

Metastatic Castration-resistant Prostate Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

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 participant 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 of blood (liquid biopsy), or tissue (de novo or archival tissue), or historical analysis (with Sponsor pre approval), of most recent tumor tissue per FoundationOne® testing. (Note: for participants enrolling in Part 1, DDR deficiency testing is optional). • Biopsies of the brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel may not be performed for the sole purpose of determining study eligibility.
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 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 androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist or antagonist for participants 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. 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 most recent PSA to be documented over a reference value (measure 1) taken at least 7 days apart within the last 12 months. 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 second measure. The third (or the fourth) confirmatory PSA should be taken within 4 weeks prior to randomization. The third (or the fourth) PSA value, obtained before randomization must be ≥1 µg/L if qualifying only by PSA progression. • Soft tissue disease progression as defined by RECIST 1.1. • Bone disease progression defined by Prostate Cancer Working Group (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 participant [or a legally acceptable representative] 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.

Exclusion criteria 10

1. Any prior systemic cancer treatment initiated in the non metastatic CRPC or mCRPC disease state. (ADT and first generation anti-androgens received in the CRPC disease state are NOT exclusionary).
2. Participants 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 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).
5. Treatment with cytotoxic chemotherapy which includes but is not limited to docetaxel, 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). Prior treatment with abiraterone in the castration-sensitive settings is not exclusionary if discontinued prior to randomization. Hormonal therapy (eg, bicalutamide, nilutamide, flutamide, estrogens) are not exclusionary if discontinued prior to randomization. Prednisone >10 mg/day (or equivalents) is exclusionary.
6. Treatment with any investigational agent within 4 weeks 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, participants can be rescreened after adequate control of blood pressure is achieved.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. * Part1: • Occurrence of target safety events.
2. *Part 2: • BICR assessed rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) in participants with mCRPC unselected for DDR status.
3. *Part 2: • BICR assessed rPFS per RECIST 1.1 (soft tissue disease) and PCWG3 (bone disease) in participants with mCRPC harboring DDR deficiencies.

Secondary endpoints 3

1. *Part1: • Multiple dose PK parameters of talazoparib and enzalutamide and its N desmethyl metabolite (Multiple dose Cmax, Ctrough, Tmax, AUC and CL/F as data permit).
2. *Part 2: • OS in participants with mCRPC unselected for DDR status (alpha protected).
3. *Part 2:• OS participants with mCRPC harboring DDR deficiencies (alpha protected).

Investigational products

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

Test 3

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 6

Locations

12 EU/EEA countries · 53 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 107 files

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

Application history

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