A Phase 2, Open-Label, 2-Arm, 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 study is to evaluate the efficacy of Talazoparib (MDV3800) in treating castration-resistant prostate cancer.

Cancer (Oncology), Cancer (Oncology) - Prostate
Song Zhao, MD, PhD

Swedish Cancer Institute

Each patient eligible to participate in this study must meet all of the following criteria:
1. At least 18 years of age and willing and able to provide informed consent.
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell, or small cell features.

3. Consent to a fresh tumor biopsy before enrollment unless adequate archival tissue is available for molecular analyses. Consent to blood sample collection for germline DNA and biomarker analysis is required.
• If the patient does not have a prior histologic diagnosis, a baseline fresh tumor biopsy may be used for both the purpose of confirming the histologic diagnosis and for biomarker analysis.• Sponsor preapproval is required when a biopsy procedure is needed for the sole purpose of determining study eligibility. Biopsies of the 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.
4. A genomic defect in a DNA repair gene that is likely to or that may sensitize to PARP inhibition as assessed by a gene mutation biomarker panel.
5. Serum testosterone ≤ 1.73 nmol/L (50 ng/dL) at screening.
6. Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist (surgical or medical castration).
7. 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.
8. Metastatic disease with measurable soft tissue disease by CT or MRI per RECIST 1.1. Patients with disease spread limited to regional pelvic lymph nodes (below the aortic bifurcation) are not eligible. Patients may also have metastatic disease documented by bone lesions on whole body radionuclide bone scan.
9. Previous treatment with 1 or 2 chemotherapy regimens including at least 1 taxane-based regimen for metastatic prostate cancer. Patients may have received radium-223 and/or cabazitaxel, or were deemed unsuitable, declined, or did not have access to these therapies.
10. A history of disease progression during previous treatment for metastatic CRPC with at least 1 novel hormonal therapy (enzalutamide and/or abiraterone acetate/prednisone) in the opinion of the investigator.
11. Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks before day 1 for patients receiving these therapies.
12. ECOG performance status of 0 to 2.
13. Estimated life expectancy of ≥ 6 months.
14. Able to swallow the study drug, have no known intolerance to study drugs or excipients, and comply with study requirements.
15. Must use a condom when having sex with a pregnant woman or with a woman of childbearing potential from the time of the first dose of study drug through 105 days after last dose of study drug. Contraception should be considered for a nonpregnant female partner of childbearing potential.
16. Must agree not to donate sperm from the first dose of study drug to 105 days after the last dose of study drug.

Each patient eligible to participate in this study must NOT meet any of the following exclusion criteria:
1. Use of systemic 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, platinum, cyclophosphamide, or mitoxantrone chemotherapy.
3. Radiation therapy within 3 weeks (within 2 weeks, if single fraction of radiotherapy) before day 1.
4. Major surgery within 2 weeks before day 1.
5. Clinically significant cardiovascular disease, including any of the following:
• Myocardial infarction or symptomatic cardiac ischemia within 6 months before screening.
• 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).
• 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.
6. Significant organ dysfunction as defined by any one of the following laboratory abnormalities:
• Renal: eGFR < 30 mL/min /1.73 m2 by the MDRD equation (Modification of Diet in Renal Disease [available via www.mdrd.com]).
• Hepatic:
– Total serum bilirubin > 1.5 times the upper limit of normal (ULN) (> 3 times ULN for patients with Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation)
– Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 2.5 times ULN (if liver test abnormalities are due to hepatic metastasis, then AST or ALT ≥ 5 × ULN)
– Albumin < 3.0 g/dL
• Bone marrow reserve: absolute neutrophil count < 1500/μL, platelets < 100,000/μL, or hemoglobin < 9 g/dL (NOTE: may not have received growth factors or blood transfusions within 14 days before obtaining the hematology values at screening).
7. Known or suspected brain metastasis or active leptomeningeal disease.
8. Symptomatic or impending spinal cord compression or cauda equina syndrome.
9. Diagnosis of MDS.
10. 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.
11. Gastrointestinal disorder affecting absorption.
12. Current or anticipated use of a strong P-gp inhibitor (eg, dronedarone, quinidine, ranolazine, itraconazole, ketoconazole), strong P-gp inducer (eg, rifampin, tipranavir, ritonavir), or strong inhibitor of BCRP (eg, elacridar [GF120918]).
13. Any other condition (concurrent disease, infection, or comorbidity) that interferes with ability to participate in the study, causes undue risk, or complic

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