The study will have 5 periods: prescreening, screening, double-blind treatment, safety
follow-up, and long-term follow-up.
Approximately 550 men with mCSPC will be randomized. Eligible participants will be randomly
assigned to either of 2 treatment groups as follows:
- Talazoparib in combination with enzalutamide.
- Placebo capsules identical in appearance to talazoparib capsules in combination with
enzalutamide.
Talazoparib or identical placebo treatment will be blinded. Enzalutamide (160 mg/day) will be
open label. The dose of talazoparib/placebo to be given in combination with enzalutamide is
0.5 mg once daily. Participants with moderate renal impairment (eGFR 30-59 mL/min/1.73 m2 by
the MDRD equation) at screening may be enrolled and the talazoparib/placebo dose will be 0.35
mg once daily.
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/µL, platelets ≥100,000/µL, 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.
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.
