A Study of Talazoparib in Men With DNA Repair Defects and Metastatic Castration-Resistant Prostate Cancer

TALAPRO-1: A PHASE 2, OPEN-LABEL, RESPONSE RATE STUDY OF TALAZOPARIB IN MEN WITH DNA REPAIR DEFECTS AND METASTATIC CASTRATION-RESISTANT PROSTATE CANCER WHO PREVIOUSLY RECEIVED TAXANE-BASED CHEMOTHERAPY AND PROGRESSED ON AT LEAST 1 NOVEL HORMONAL AGENT (ENZALUTAMIDE AND/OR ABIRATERONE ACETATE/PREDNISONE)

The purpose of this international, phase 2, open-label, response rate study of talazoparib is to assess the efficacy and safety of talazoparib in men with DNA repair defects metastatic castration-resistant prostate cancer (CRPC) who previously received taxane-based chemotherapy and progressed on at least 1 novel hormonal agent (enzalutamide and/or abiraterone acetate/prednisone).

Inclusion Criteria:

1. At least 18 years of age.

2. Histologically or cytologically confirmed adenocarcinoma of the prostate without signet cell, or small cell features.

3. Patients must have measurable soft tissue disease per RECIST 1.1

4. DNA damage repair deficiency as assessed centrally by a gene mutation biomarker panel (testing of de novo or archival tumor tissue (via central laboratory) or prior historical testing (with Sponsor approval) using the Foundation Medicine, FoundationOne CDx™ NGS gene panel test.

5. Consent to a saliva sample collection for a germline comparator, unless prohibited by local regulations or ethics committee (EC) decision.

6. Serum testosterone ≤ 1.73 nmol/L (50 ng/dL) at screening.

7. Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist (surgical or medical castration).

8. Progressive disease at study entry defined as 1 or more of the following 3 criteria:

   • A minimum of 3 rising PSA values with an interval of at least 1 week between determinations. The screening central laboratory PSA value must be ≥ 2 μg/L (2 ng/mL) if qualifying solely by PSA progression.
   • Soft tissue disease progression as defined by RECIST 1.1.
   • Bone disease progression defined by PCWG3 with 2 or more new metastatic lesions on bone scan.

9. Metastatic disease.

10. Previous treatment with 1 or 2 chemotherapy regimens including at least 1 taxane-based regimen for metastatic (non castrate or castrate) prostate cancer. Patients may have received radium-223 and/or cabazitaxel, or were deemed unsuitable, declined, or did not have access to these therapies.

11. Documented disease progression (either radiographic or biochemical) on at least 1 novel hormonal therapy (enzalutamide and/or abiraterone acetate/prednisone) for the treatment of metastatic CRPC, irrespective of prior NHT treatment for non castrate prostate cancer or nonmetastatic (M0) CRPC.

12. Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks before day 1 for patients receiving these therapies.

13. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

14. Estimated life expectancy of ≥ 6 months as assessed by the investigator.

15. Able to swallow the study drug, have no known intolerance to study drugs or excipients, and comply with study requirements.

16. Must use a condom when having sex from the time of the first dose of study drug through 4 months after last dose of study drug. A highly effective form of contraception must be used from the time of the first dose of study drug through 4 months after last dose of study drug when having sex with a non pregnant female partner of childbearing potential.

17. Must agree not to donate sperm from the first dose of study drug to 4 months after the last dose of study drug.

18. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

Exclusion Criteria:

1. 1. Use of systemic chemotherapeutic (including but not limited to taxanes), hormonal, biologic, or radionuclide therapy for treatment of metastatic prostate cancer (other than approved bone targeting agents and GnRH agonist/antagonist) or any other investigational agent within 4 weeks before day 1.
2. Prior treatment with a PARP inhibitor, cyclophosphamide, or mitoxantrone chemotherapy. Patients who discontinued prior platinum based chemotherapy <=6 months prior to screening or whose disease previously progressed on platinum based therapy at any time in the past are also excluded.
3. Treatment with any concurrent cytotoxic chemotherapy or investigational drug(s) within 4 weeks or 5 half lives of the drug (whichever is longer) before Day 1 and/or during study participation
4. Radiation therapy within 3 weeks (within 2 weeks, if single fraction of radiotherapy) before day 1.
5. Major surgery within 2 weeks before day 1.
6. Clinically significant cardiovascular disease.
7. Significant renal, hepatic, or bone marrow organ dysfunction.
8. Known or suspected brain metastasis or active leptomeningeal disease.
9. Symptomatic or impending spinal cord compression or cauda equina syndrome.
10. Prior diagnosis of myelodysplastic syndrome or acute myeloid leukemia
11. History of another cancer within 3 years before enrollment with the exception of nonmelanoma skin cancers, or American Joint Committee on Cancer stage 0 or stage 1 cancer that has a remote probability of recurrence in the opinion of the investigator and the sponsor.
12. Gastrointestinal disorder affecting absorption.
13. Current or anticipated use within 7 days prior to first dose of study drug or anticipated use during the study of the following P gp inhibitors (amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, verapamil, and valspodar).
14. Any other acute or chronic medical or psychiatric condition (concurrent disease, infection, or comorbidity) that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of data, in the opinion of the investigator or sponsor, including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
15. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
16. Fertile male subjects who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 4 months after the last dose of investigational product.