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

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Talazoparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age. Histologically or cytologically confirmed adenocarcinoma of the prostate without signet cell, or small cell features. Patients must have measurable soft tissue disease per RECIST 1.1 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. Consent to a saliva sample collection for a germline comparator, unless prohibited by local regulations or ethics committee (EC) decision. Serum testosterone ≤ 1.73 nmol/L (50 ng/dL) at screening. Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist (surgical or medical castration). 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. Metastatic disease. 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. 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. Bisphosphonate or denosumab dosage must have been stable for at least 4 weeks before day 1 for patients receiving these therapies. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Estimated life expectancy of ≥ 6 months as assessed by the investigator. Able to swallow the study drug, have no known intolerance to study drugs or excipients, and comply with study requirements. 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. Must agree not to donate sperm from the first dose of study drug to 4 months after the last dose of study drug. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures. Exclusion Criteria: 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. 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. 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 Radiation therapy within 3 weeks (within 2 weeks, if single fraction of radiotherapy) before day 1. Major surgery within 2 weeks before day 1. Clinically significant cardiovascular disease. Significant renal, hepatic, or bone marrow organ dysfunction. Known or suspected brain metastasis or active leptomeningeal disease. Symptomatic or impending spinal cord compression or cauda equina syndrome. Prior diagnosis of myelodysplastic syndrome or acute myeloid leukemia 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. Gastrointestinal disorder affecting absorption. 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). 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. 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Talazoparib<br>Talazoparib 1 mg daily | Drug: Talazoparib<br>* 1 mg daily<br>* Other names: MDV3800;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Objective Response Rate (ORR) | Best ORR was defined as the percentage of participants with best overall soft tissue response of complete response (CR) or partial response (PR) as per RECIST1.1 by an independent central review. RECIST 1.1 criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than 10 millimeter (mm). Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (less than 10 mm short axis); PR: at least 30 percent (%) decrease in sum of diameters of target lesions taking as reference baseline sum diameters. | From first dose of study drug to best overall soft tissue response CR or PR (maximum duration of 25 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Objective Response | Time to objective response was defined as the time from first dose of talazoparib to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per prostate cancer working Group 3 (PCWG3). Soft tissue response is defined as a best overall response of CR or PR per RECIST 1.1 by independent central review. RECIST 1.1 criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than 10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (less than 10 mm short axis); PR: at least 30 % decrease in sum of diameters of target lesions taking as reference baseline sum diameters. | From first dose of study drug to first objective response (maximum duration of 25 months) | 
| Duration of Response (DOR) | DOR was defined as the time from the first objective evidence of soft tissue response (CR or PR, whichever is earlier) per RECIST 1.1 and no evidence of confirmed bone disease progression per PCWG3 to the date of first objective evidence of radiographic progression or death due to any cause without evidence of radiographic progression, whichever occurs first. RECIST 1.1 criteria, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than 10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (less than 10 mm short axis); PR: at least 30 % decrease in sum of diameters of target lesions taking as reference baseline sum diameters. | From the first objective evidence of soft tissue response (CR or PR, whichever is earlier) to radiographic progression or death due to any cause without evidence of radiographic progression, whichever occurs first (maximum duration of 25 months) | 
| Percentage of Participants With Prostate-Specific Antigen (PSA) Response of Greater Than or Equal to (>=) 50 Percent (%) | Analysis is not final for this outcome measure at PCD, complete data will be posted at study completion date (SCD). | Approximately 56 months | 
| Percentage of Participants With Circulating Tumor Cell (CTC) Count Greater Than or Equal to (>=) 5 Circulating Tumor Cell (CTC) Per 7.5 Milliliter (mL) of Blood at Baseline Decreasing to Less Than (<) 5 CTC of Blood Any Time on Study | Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD. | Approximately 56 months | 
| Percentage of Participants With Circulating Tumor Cell (CTC) Count >=1 CTC Per 7.5 mL of Blood at Baseline Decreasing to Null CTC of Blood Any Time on Study | Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD. | Approximately 56 months | 
| Percentage of Participants With Circulating Tumor Cell (CTC) Count <5 CTC Per 7.5 mL of Blood at Baseline Increased Any Time on Study | Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD. | Approximately 56 months | 
| Time to Prostate-Specific Antigen (PSA) Progression | Time to PSA progression was defined as the time from first dose of study treatment to the date of PSA progression, which was subsequently confirmed. Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD. | Approximately 56 months | 
| Radiographic Progression-Free Survival (PFS) | Radiographic PFS was defined as the time from date of first dose of talazoparib to first objective evidence of radiographic progression as assessed in soft tissue per modified RECIST 1.1 or confirmed progression in bone per PCWG3 guidelines by independent central review or death without documented radiographic progression, whichever occurs first. | From date of first dose of study drug to first objective evidence of radiographic progression or death without documented radiographic progression, whichever occurs first (maximum duration of 25 months) | 
| Overall Survival (OS) | OS was defined as the time from the first dose of study treatment to death due to any cause. For participants who were alive, OS was censored at the last contact. Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD. | Approximately 56 months | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to 28 days after last dose of study drug (approximately up to 26 months) | 
| Number of Participants With Permanent Treatment Discontinuation Due to Adverse Events | Treatment discontinuation was defined as permanent cessation of study drug treatment administration. | Baseline up to 28 days after last dose of study drug (approximately up to 26 months) | 
| Number of Participants With Clinically Significant Abnormalities in Vital Signs | Vital sign abnormalities criteria included: 1) Systolic blood pressure (SBP) in millimeters of mercury (mmHg): absolute result greater than (>) 180 mmHg and increase from baseline greater than or equal to (>=) 40 mmHg or absolute result < 90 mmHg and decrease from baseline > 30 mmHg; 2) Diastolic blood pressure (DBP) (mmHg): absolute result > 110 mmHg and increase from baseline >= 30 mmHg or absolute result < 50 mmHg and decrease from baseline > 20 mmHg or >= 20 mmHg increase from baseline; 3) Heart rate in beats per minutes (bpm): absolute result < 50 bpm and decrease from baseline > 20 bpm or absolute result > 120 bpm and increase from baseline > 30 bpm; Weight in kilogram: > 10% decrease from baseline. | Baseline up to 28 days after last dose of study drug (approximately up to 26 months) | 
| Number of Participants With Shift in Laboratory Parameter Values (Hematology) From Grade <=2 at Baseline to Grade 3 or 4 Post-baseline | Hematology parameters included anemia, hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased and white blood cell decreased. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. | Baseline up to 28 days after last dose of study drug (approximately up to 26 months) | 
| Number of Participants With Shift in Laboratory Parameter Values (Chemistry) From Grade <=2 at Baseline to Grade 3 or 4 Post-baseline | Chemistry parameters:alanine aminotransferase increased(inc), alkaline phosphatase inc, aspartate aminotransferase inc, blood bilirubin inc, chronic kidney disease, creatinine inc, gamma-glutamyl transferase (GGT) inc, hypercalcemia, hypercalcemia, hyperkalemia, hypermagnesemia, hypermagnesemia, hypermagnesemia, hypocalcemia, hypocalcemia, hypokalemia, hypomagnesemia, hypophosphatemia and hypophosphatemia. Severity was graded as G1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; G2:moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G3:severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; G4:life-threatening consequence, urgent intervention indicated; G5: death related to AEs. | Baseline up to 28 days after last dose of study drug (approximately up to 26 months) | 
| Number of Participants With Dose Modification | Number of participants with dose modification due to adverse events was reported. | Baseline up to 28 days after last dose of study drug (approximately up to 26 months) | 
| Time to Deterioration in Pain Symptom Scores | Time to deterioration in pain symptom scores was assessed by brief pain inventory short form (BPI-SF). Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD. | Approximately 56 months | 
| Change From Baseline in Participant Reported Pain Scores Per BPI-SF Till End of the Study | BPI-SF is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions. BPI-SF are 4 questions that assess pain intensity (worst, least, average, right now) and 7 questions that assess impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each question is answered on a scale ranging from 0 to 10; '0=No pain and 10=Pain as bad as you can imagine'. Measure can be scored by item, with lower scores being indicative of less pain or pain interference. Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD. | Approximately 56 months | 
| Change From Baseline in Patient-Reported Health-Related Quality of Life as Assessed by European Quality of Life 5-Domain 5-Level Scale (EQ-5D-5L) Scores Till End of the Study | The EQ-5D-5L consists of two sections, the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS).The EQ-5D descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression with five response levels for each dimension: no problems, slight problems, moderate problems, severe problems and extreme problems. The EQ-5D VAS is a 20 cm vertical scale where patients can mark from 0 (worst health imaginable) to 100 (best health imaginable). Overall scores range from 0 to 1, with low scores representing a higher level of dysfunction. Analysis is not final for this outcome measure at PCD, complete data will be posted at SCD. | Approximately 56 months | 
| Pre-dose Plasma Concentration (Ctrough) of Talazoparib | Ctrough was defined as pre-dose plasma concentration during dosing and observed directly from data. | Pre-dose at Week 1, 5, 9 and 13 | 
| Post-dose Plasma Concentration (Ctrough) of Talazoparib | Plasma concentration was measured 2 hours after dosing and observed directly from data. | 2 hours post-dose at Week 1 and 5 |