Study of Talazoparib With Enzalutamide in Men With DDR Gene Mutated mCSPC

JRCT ID: jRCT2031210098

Registered date:18/05/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Metastatic Castration-sensitive Prostate Cancer
• Date of first enrollment: 31/05/2021
• Target sample size: 550
• Countries of recruitment: United States,Japan,Korea, Republic of,Japan
• Study type: Interventional

Intervention(s)

Drug: Experimental arm
talazoparib plus enzalutamide
Other Name: Combination arm

Drug: Active comparator arm
Placebo plus enzalutamide
Other Name: Monotherapy arm

Outcome(s)

Primary Outcome

Primary Outcome Measures :
1.radiological Progression-Free Survival [ Time Frame: randomization up to 3 years ]
time from the date of randomization to first objective evidence of radiographic progression or death, whichever occurs first

Secondary Outcome

Secondary Outcome Measure :
1.Overall Survival [ Time Frame: randomization up to 4 years ]
time from randomization to death from any cause
2.Objective response in measurable soft tissue disease [ Time Frame: randomization up to 3 years ]
proportion of patients with measurable soft tissue disease at baseline with objective response per RECIST 1.1
3.Duration of response in measurable soft tissue disease [ Time Frame: randomization up to 3 years ]
duration of responses in patients with measurable soft tissue disease at baseline per RECIST 1.1
4.Prostate Specific Antigen (PSA) response [ Time Frame: randomization up to 3 years ]
proportion of patients with PSA response grater than or equal to 50%
5.Time to PSA progression [ Time Frame: randomization up to 3 years ]
time from baseline to PSA progression
6.Time to initiation of antineoplastic therapy [ Time Frame: randomization up to 3 years ]
Time from randomization to initiation of antineoplastic therapy
7.Time to first symptomatic skeletal event [ Time Frame: randomization up to 3 years ]
time from randomization to first symptomatic skeletal event (symptomatic fractures, spinal cord compression, surgery or radiation to the bone whichever is first)
8.Opiate use for prostate cancer pain [ Time Frame: randomization up to 3 years ]
time from randomization to opiate use for prostate cancer pain
9.Incidence of adverse events [ Time Frame: randomization up to 3 years ]
AEs and SAEs incidence by type and severity (graded by NCI CTCAE version 4.03)
10.Pharmacokinetic assessment of talazoparib [ Time Frame: Weeks 5, 9, 13, and 17 ]
plasma concentrations of talazoparib
11.Pharmacokinetic assessment of enzalutamide and its metabolite [ Time Frame: Weeks 5, 9, 13, and 17 ]
plasma concentrations of enzalutamide and its metabolite
12.Relationship between ctDNA burden and outcome [ Time Frame: randomization up to 3 years ]
ctDNA burden at baseline and on study
13.Patient-reported outcomes in pain symptoms - change from baseline [ Time Frame: randomization up to 3 years ]
change from baseline in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF)
14.Patient-reported outcomes in pain symptoms - time to deterioration [ Time Frame: randomization up to 3 years ]
time to deterioration in patient-reported pain symptoms per Brief Pain Inventory Short Form (BPI-SF)
15.Patient-reported outcomes in cancer specific general health status - change from baseline [ Time Frame: randomization up to 3 years ]
change from baseline in participant-reported general health status per EQ-5D-5L
16.Patient-reported outcomes in cancer specific global health status/QoL - change from baseline [ Time Frame: randomization up to 3 years ]
change from baseline in patient-reported Global health status/QoL per EORTC QLQ-C30
17.Patient-reported outcomes in cancer specific global health status/QoL - time to definitive deterioration [ Time Frame: randomization up to 3 years ]
time to definitive deterioration in patient-reported global health status/QoL per EORTC QLQ-C30
18.Patient-reported outcomes in cancer specific symptoms - time to definitive deterioration [ Time Frame: randomization up to 3 years ]
time to definitive deterioration in disease specific urinary symptoms per EORTC QLQ-PR25
19.Patient-reported outcome: cancer specific functioning, and symptoms - change from baseline [ Time Frame: randomization up to 3 years ]
change from baseline in PGI-S

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: <= 99age old
• Gender: Male

Include criteria

Inclusion Criteria:
1.Male participants at least 18 years of age at screening (20 years for Japan).
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 may also be used to support biomarker analysis.
3.Confirmation of DDR gene mutation status by prospective or historical analysis (with sponsor pre-approval) of blood (liquid biopsy) and/or de novo or archival tumor tissue using FoundationOne Liquid CDx or FoundationOne CDx.
4.Willing to provide tumor tissue when available (de novo or archived) for retrospective molecular profiling analysis, if not already provided as part of inclusion criterion 3.
5.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 less or equal to 50 ng/dL (less or equal to 1.73 nmol/L) at screening. Ongoing ADT with a GnRH agonist or antagonist for participants who have not undergone bilateral orchiectomy must be initiated at least 4 weeks before randomization and must continue throughout the study.
7.Metastatic prostate cancer documented by positive bone scan (for bone disease) or metastatic lesions on CT or MRI scan (for soft tissue). Participants whose disease spread is limited to regional pelvic lymph nodes are not eligible. Note: a finding of superscan at baseline is exclusionary.
8.Prior docetaxel therapy for mCSPC (up to 6 cycles) is allowed (must be completed 2 weeks prior to randomization and all toxicities from treatment have resolved).
9.Treatment with estrogens, cyproterone acetate, or first-generation anti-androgens is allowed until randomization.
10.Other prior therapy allowed for mCSPC; <=6 months of ADT and <=3 months of approved NHT in mCSPC (ie, abiraterone + prednisone, apalutamide, or enzalutamide), if required prior to randomization.
11.Participant may have received palliative radiation or surgery for symptomatic control secondary to prostate cancer, which should have been completed at least 2 weeks prior to randomization.
12.ECOG performance status 0 or 1.
13.Adequate organ function within 28 days before the first study treatment on Cycle 1 Day 1, defined by the following:
*ANC >=1500/mm3L, platelets >=100,000/mm3L, or hemoglobin >=9 g/dL (may not have received growth factors or blood transfusions within 14 days before obtaining the hematology laboratory tests at screening).
*Total serum bilirubin <1.5 * ULN (<3 * ULN for participants with documented Gilbert syndrome or for whom indirect bilirubin concentrations suggest an extrahepatic source of elevation).
*AST or ALT <2.5 * ULN (<5 * ULN if liver function abnormalities are due to hepatic metastasis).
*Albumin >2.8 g/dL.
*eGFR >=30 mL/min/1.73 m2 by the MDRD equation.
14.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 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.
15.Must agree not to donate sperm from the first dose of study treatment to 4 months after the last dose of study treatment.
16.Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
17.Capable of giving signed informed consent.

Exclude criteria

Exclusion Criteria:
1.Other acute or chronic medical (concurrent disease, infection or co-morbidity) or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that interferes with a participant's ability to participate in the study, may increase the risk of associated with study participation or study treatment administration, or may interfere with the interpretation of study results, and, in the investigator's judgment, make the participant inappropriate for entry into the study.
2.History of seizure or any condition (as assessed by investigator) that may predispose to seizure (eg, prior cortical stroke, significant brain trauma), including any history of loss of consciousness or transient ischemic attack within 12 months of randomization.
3.Major surgery (as defined by the investigator) within 2 weeks before randomization.
4.Known or suspected brain metastasis or active leptomeningeal disease.
5.Symptomatic or impending spinal cord compression or cauda equina syndrome.
6.Any history of MDS, AML, or prior malignancy except for the following:
*Carcinoma in situ or non-melanoma skin cancer.
*A cancer diagnosed and treated >=3 years before randomization with no subsequent evidence of recurrence.
*American Joint Committee on Cancer Stage 0 or Stage 1 cancer <3 years before randomization that has a remote probability of recurrence in the opinion of the investigator and the sponsor.
7.In the opinion of the investigator, any clinically significant gastrointestinal disorder affecting absorption.
8.Clinically significant cardiovascular disease, including any of the following:
*Myocardial infarction or symptomatic cardiac ischemia within 6 months before randomization.
*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.
9.Active COVID-19 infection detected by viral test or based on clinical diagnosis (as assessed by investigator). Asymptomatic participants with no active COVID-19 infection detected but positive antibody tests, indicating past infection are allowed.
10.Prior ADT in the adjuvant/neoadjuvant setting, where the completion of ADT was less than 12 months prior to randomization and the total duration of ADT exceeded 36 months.
11.Participant received treatment with systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone within 4 weeks prior to randomization, intended for the treatment of prostate cancer.
12.Any previous treatment with DNA-damaging cytotoxic chemotherapy (ie, platinum based therapy) within 5 years prior to randomization, except for indications other than prostate cancer.
13.Prior treatment with a PARPi.
14.Prior treatment in any setting with NHT, except as described in Inclusion Criterion #10.
15.Current use of potent P-gp inhibitors within 7 days prior to randomization. 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 6.5.
16.Treatment with any investigational study intervention within 4 weeks before randomization. Exception: COVID-19 vaccines authorized under an emergency use authorization (or equivalent) can be administered without a washout period.
17.Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, QTcF interval >450 msec, complete LBBB, signs of an acute or indeterminate age myocardial infarction, ST-T interval changes suggestive of myocardial ischemia, second or third degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If the baseline uncorrected QT interval is >450 msec, this interval should be rate-corrected using the Fridericia method and the resulting QTcF should be used for decision making and reporting. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTc or QRS values should be used to determine the participant's eligibility. Computer-interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants.
18.Investigator site staff or Sponsor employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.

Related Information

• Primary Sponsor: Kawai Norisuke
• Secondary ID(s): NCT04821622