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

Pfizer128 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

128

Conditions

Prostate Cancer

Interventions

TalazoparibDRUG

1 mg daily

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (120)

Outcomes

Primary Outcomes

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.

Time frame: From first dose of study drug to best overall soft tissue response CR or PR (maximum duration of 25 months)

Secondary Outcomes

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.

Time frame: 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.

Data from ClinicalTrials.gov

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Arizona Oncology Associates

Tempe, Arizona, United States

City of Hope (City of Hope National Medical Center, City of Hope Medical Center)

Duarte, California, United States

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Lancaster, California, United States

UC Irvine Health Investigational Drug Pharmacy

Orange, California, United States

University of California, Irvine Medical Center

Orange, California, United States

Medical Oncology Associates-SD

San Diego, California, United States

Sharp Outpatient Infusion Therapy Center

San Diego, California, United States

Sharp Rees-Stealy

San Diego, California, United States

Emory University Hospital

Atlanta, Georgia, United States

The Emory Clinic

Atlanta, Georgia, United States

...and 110 more locations

Time frame: 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 Percentage (%)

Percentage of participants with PSA response of \>= 50% was reported in this outcome measure. PSA response was calculated as a decline from baseline PSA (ng/mL) by at least 50% measured by central laboratory.

Time frame: From the date of first dose of study treatment until confirmed PSA progression or start of new anticancer treatment given after the first dose of study treatment (maximum duration of 25 months)

Percentage of Participants With Conversion of Circulating Tumor Cell (CTC) Count

Percentage of participants with conversion of CTC count was defined as percentage of participants with a CTC count \>= 5 CTC per 7.5 milliliter (mL) of blood at baseline that decreased to \< 5 CTC per 7.5 mL of blood any time on study.

Time frame: Baseline to anytime on study during final analysis of the outcome measure, up to maximum duration of 25 months

Percentage of Participants With a Null CTC Count

Percentage of participants with a null CTC count was defined as percentage of participants with CTC count \>=1 CTC per 7.5 mL of blood at baseline that decreased to CTC = 0 per 7.5 mL of blood any time on study.

Time frame: Baseline to anytime on study during final analysis of the outcome measure, up to maximum duration of 25 months

Percentage of Participants With Baseline CTC Count <5 CTC Showed Increased CTC Counts at Any Time on Study

Percentage of participants with CTC count \<5 CTC per 7.5 mL of blood at baseline those who showed an increased CTC count, compared to baseline, any time on study was reported in this study.

Time frame: Baseline to anytime on study during final analysis of the outcome measure, up to maximum duration of 25 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. The time from first dose of talazoparib to the date that a \>=25% increase in PSA with an absolute increase of \>=2micogram per liter (2 nanogram per mL) above the nadir (or baseline for participants with no PSA decline) was documented, confirmed by a second consecutive PSA value obtained \>=3 weeks (21 days) later. Kaplan-Meier method was used for analysis.

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.

Time frame: 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 start date (the date of first dose of treatment) to the date of death due to any cause. Participants who had not died were censored at the date of last contact. Kaplan-Meier method was used for analysis.

Time frame: From first dose of study treatment up to death due to any cause during study or date of last contact (approximately 36 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. AEs included both serious AEs and all non-serious AEs. 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.

Time frame: First dose of study drug up to 28 days after last dose of study drug (study treatment was approximately for 36 months, safety follow up to approximately 37 months)

Number of Participants With Permanent Treatment Discontinuation Due to Adverse Events

Treatment discontinuation was defined as permanent cessation of study drug treatment administration.

Time frame: During study treatment (approximately up to 36 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.

Time frame: During study treatment (approximately up to 36 months)

Number of Participants With Shift in Laboratory Parameter Values (Hematology) From Grade Less Than Equal to (<=) 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, Leukocytosis 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 non-invasive 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.

Time frame: During study treatment (approximately up to 36 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, Hyperglycemia, hyperkalemia, hypermagnesemia, hypocalcemia, Hyponatremia, hypoglycemia, hypokalemia, hypomagnesemia, hypernatremia, Hypoalbuminemia and hypophosphatemia. Severity was graded as Grade(G)1: 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.

Time frame: During study treatment (approximately up to 36 months)

Number of Participants With Dose Modification

Number of participants with dose modification due to adverse events was reported.

Time frame: During study treatment (approximately up to 36 months)

Time to Deterioration in Pain Symptom Scores

Time deterioration is based on BPI-SF question 3: "Please rate your pain by marking the box beside the number that best describes your pain at its worst in the last 24 hours." Pain intensity was to be answered on a range of 0 to 10, where 0 corresponded to no pain and 10 worst pain. Time to this event is defined as the time from the date of first dose of study treatment to onset of pain progression, where pain progression is defined as a 2-point or more increase from baseline in the question 3 score. Kaplan-Meier method was used for analysis. Average of all assessments visits is reported in this outcome measure.

Time frame: Baseline till final analysis of the outcome measure, up to maximum duration of 25 months

Change From Baseline in Participant Reported Pain Scores Per BPI-SF Question 3

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 have 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. BPI-SF question 3 was related to participant experiencing pain at its worst in last 24 hours, score range 0 to 10, where large values corresponded to worse outcomes.

Time frame: Baseline, Week 1, 3, 5, 7, 9, 13, 17, 21, 25, 37, 49, 61, 73, 85, Follow-up Visit (28 days after last dose) [maximum duration of 25 months]

Change From Baseline in European Quality of Life 5-Domain 5-Level Scale (EQ-5D-5L) Visual Analogue Scores (VAS)

The EQ-5D VAS score was a participant rated questionnaire where participants rated how they felt at assessment visit on a vertical VAS that ranged from 0 (worst imaginable health state) to 100 (best imaginable health state), with higher scores indicating a better health condition.