A Phase III, Randomized, Double-blind, Placebo-controlled Study Of Talazoparib With Enzalutamide In Metastatic Castration-resistant Prostate Cancer
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Study Summary
To assess radiographic PFS in men with mCRPC (with no systemic treatments initiated after documentation of mCRCP) treated with talazoparib and enzalutamide vs. placebo plus enzalutamide
Part 1:
To confirm the starting dose of talazoparib in combination with each enzalutamide through assessment of target safety events and PK at select sites.
Part 2:
To compare talazoparib plus enzalutamide vs. placebo plus enzalutamide in patients with mCRPC.
Efficacy will be assessed by radiographic assessments every 8 wks through week 25 and every 8-12 wks thereafter.
To demonstrate that talazoparib in combination with enzalutamide is superior to placebo in combination with enzalutamide in prolonging BICR assessed rPFS, in patients with mCRPC unselected for DDR status.
To evaluate the efficacy, safety, pharmacokinetics and (patient) pt-reported outcomes of the combination treatment of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA.
To evaluate the Talazoparib and enzalutamide are superior to placebo and enzalutamide in prolongs rPFS in mCRPC patients with no choice for DDR status.
To evaluate the Talazoparib and enzalutamide are superior to placebo and enzalutamide prolongs rPFS in mCRPC patients with DDR deficiency.
To compare the rPFS in men with mCRPC treated with talazoparib plus enzalutamide vs. enzalutamide after confirmation of the starting dose of talazoparib in combination with enzalutamide.
To evaluate efficacy, safety, pharmacokinetics, and patient-reported outcomes (PROs) of TALA combined with ENZA.
Efficacy is assessed radiographically every 8 weeks up to Week 25 and every 8–12 weeks thereafter. rPFS will be compared between the two arms
To provide a detailed overview of the safety profile of talazoparib plus enzalutamide in the all-comers population of the TALAPRO-2 trial with the aim of understanding how adverse events were managed
To evaluate talazoparib plus enzalutamide as a first-line treatment in patients with mCRPC, demonstrated statistically significant and clinically meaningful improvement in radiographic progression-free survival vs placebo plus enzalutamide in an all-comers population unselected for HRR gene alterations (hazard ratio=0.63; 95% CI, 0.51-0.78; P<0.0001)
Prospective testing used a 12-gene HRR panel (HRR12) of FoundationOne CDx/FoundationOne Liquid CDx.For single gene groups, only pts bearing alteration(s) in that gene and no other HRR12 genes were analyzed.
Endpoints: ORR, time to progression or death on first subsequent antineoplastic therapy (PFS2), PSA response ≥50%, time to PSA progression (TTPP), and time to initiation of cytotoxic chemotherapy (TTCC)
To analyses of homologous recombination repair (HRR) gene subgroups and potential associations with secondary efficacy endpoints in the HRR-deficient population
Safety assessments
The safety population included patients who received at least one dose of study drug. Safety analyses evaluated the most common treatment-emergent adverse events (TEAEs), type, severity, timing, seriousness, and relationship to study treatment.
Adverse events were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03 [14]. Adverse events of special interest (AESI) were acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), pneumonitis, venous thromboembolism, and second primary nonhematologic malignancies.
Preferred terms were clustered to better assess hematologic TEAEs where indicated. Anemia: anemia, hematocrit decreased, hemoglobin decreased, red blood cell count decreased. Neutropenia: neutropenia, neutrophil count decreased. Thrombocytopenia: thrombocytopenia, platelet count decreased. Leukopenia: leukopenia, white blood cell count decreased. Lymphopenia: lymphopenia, lymphocyte count decreased.
The objective of this study was to assess the relative efficacy between TALA + ENZA (TALAPRO-2) versus OLAP + AAP (PROpel) and NIRA + AAP (MAGNITUDE) in 1 L mCRPC via a matching-adjusted indirect treatment comparison (MAIC).
To report updated final PROs for the unselected cohort.
To predict incidence of grade (G)≥3 anemia in pts receiving TALA 0.5 mg (0.35 mg, moderate renal impairment) + ENZA in TALAPRO-2.
Baseline (BL) pt and disease characteristics were used to predict G≥3 anemia after TALA initiation using ML models (least absolute shrinkage and selection operator [LASSO] Cox regression, extreme gradient boosting [XGB], survival support vector machine [SVM]). A longitudinal time-varying model was created by further including post-BL hemoglobin measures. Accuracy between models was compared using area under receiver operating characteristic curve (AUC) based on 3-fold cross-validation (CV). Data were truncated at the first of: red blood cell transfusion, dose modification, subsequent antineoplastic tx initiation, date of last contact, death, or data cutoff.
- At least 18 years of age. For Japan, at least 20 years of age.
- Histologically or cytologically confirmed adenocarcinoma of the prostate without small cell or signet cell features
- Asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) (score on BPI-SF Question #3 must be < 4).
- For enrollment into Part 2 only (optional in Part 1): assessment of DDR mutation status
- Consent to a saliva sample collection for a germline comparator unless prohibited by local regulations or ethics committee decision (optional for patients in Part 1).
- Surgically or medically castrated, with serum testosterone < or = 50 ng/dL (< or = 1.73 nmol/L) at screening.
- Metastatic disease in bone documented on bone scan or in soft tissue documented on CT/MRI scan.
- Progressive disease at study entry in the setting of medical or surgical castration as defined by 1 or more of the following 3 criteria:
- Prostate specific antigen (PSA) progression defined by a minimum of 2 rising PSA values from 3 consecutive assessments with an interval of at least 7 days between assessments..
- Soft tissue disease progression as defined by RECIST 1.1.
- Bone disease progression defined by Prostate Cancer Working Group 3 (PCWG3) with 2 or more new metastatic bone lesions on a whole body radionuclide bone scan.
- Ongoing bisphosphonate or denosumab use prior to Day 1 (Part 1) or randomization (Part 2) is allowed but not mandatory.
- Eastern Cooperative Oncology Group (ECOG) performance status < or = 1.
- Life expectancy > or = 12 months as assessed by the investigator.
- Able to swallow the study drug and have no known intolerance to study drugs or excipients.
- Must agree to use a condom when having sex with a partner from the time of the first dose of study drug 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.
- Must agree not to donate sperm from the first dose of study drug to 4 months after the last dose of study drug.
- Evidence of a personally signed and dated informed consent document (and molecular prescreening consent if appropriate) indicating that the patient [or a legally acceptable representative/legal guardian] has been informed of all pertinent aspects of the study.
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
- Prostate adenocarcinoma with non-small cell or signet ring cell characteristics diagnosed histologically or cytologically. If the patient has no previous histological diagnosis, a fresh baseline biopsy sample must be used to confirm the diagnosis and support biomarker analysis.
- Participation only part 2 (optional part 1): Assess DDR mutation status through prospective analysis of fresh tumor tissue (fresh or archived tissue) or historical analysis (pre-approved by the sponsor) in accordance with the FoundationOne. Trial . (Note: DDR deficiency testing is optional for patients participating in Part 1.) Biopsy of the brain, lungs / mediastinum, pancreas, or esophagus, stomach, or intestinal tract must not be performed just to determine eligibility for study enrollment Other than endoscopy.
- Participation only in Part 2 (optional part 1): Unless prohibited by local regulations or determined by the Ethics Committee, agree to take a saliva sample for review of the same DDR gene or some of it in tumor tissue Sex sequencing, and as a control for identifying germline mutations in tumor mutations.
- Castrate by surgery or medication, and testosterone levels at screening. 50 ng / dL (. 1.73 nmol / L). Alternatively, androgen deprivation therapy is being performed with a gonadotropin-releasing hormone (GnRH) agonist or antagonist in patients who have not undergone bilateral orchiectomy, but such treatment must be on Day 1 (Part 1) Begin at least 4 weeks before randomization (Part 2) and treatment must be maintained throughout the study period.
- Bone scan results indicate metastatic lesions in bones, or CT / MRI scan results indicate metastatic lesions in soft tissue. In cases where the scan meets the study requirements, scan results obtained during the standard treatment period on Day 1 (Part 1) or 6 weeks (42 days) before randomization (Part 2) can be used. It is not necessary to have an assessable soft tissue lesion. (Only patients with adenocarcinoma below the aortic bifurcation are not eligible.)
- In the case of castration with drugs or surgery, participants who participated in the study had progressive disease defined by one or more of the following 3 criteria: Prostate Specific Antigen (PSA) Progression, defined as a recorded increase in PSA of at least consecutive 2 Times (at least 7 days apart) above the reference value (measured value 1). If the third PSA measurement value is not higher than the second measurement value, the fourth PSA measurement is required, and the measurement value is higher than the second measurement value. A 3rd (or 4th) confirmatory PSA determination should be performed within 4 weeks before randomization. The initial PSA value must be = 1 µg / L. Soft tissue disease progression, as defined in RECIST 1.1. Progression of bone disease as defined by the Prostate Cancer Working Group 3 (PCWG3), with 2 or more new metastatic bone lesions on a systemic radionuclide bone scan
- Age >or= 18 y, asymptomatic/mildly symptomatic mCRPC, ECOG performance status
- Prior therapies (excluding novel AR inhibitors) in the castration-sensitive (CSPC) setting are allowed.
- Eastern Cooperative Oncology Group performance status score of 0 or 1, receiving ongoing androgen deprivation therapy or had undergone surgical
- orchiectomy, and progressive disease at study entry. Prior docetaxel and abiraterone or orteronel in the castration-sensitive setting were allowed.
- Any prior systemic cancer treatment initiated in in the non metastatic CRPC and mCRPC disease state.
- Patients whose only evidence of metastasis is adenopathy below the aortic bifurcation.
- Prior treatment with second-generation androgen receptor inhibitors (enzalutamide, apalutamide, and darolutamide), a PARP inhibitor, cyclophosphamide, or mitoxantrone for prostate cancer.
- Prior treatment with platinum-based chemotherapy within 6 months (from the last dose) prior to Day 1 (Part 1) or randomization (Part 2), or any history of disease progression on platinum-based therapy within 6 months (from the last dose).
- Treatment with cytotoxic chemotherapy, biologic therapy including sipuleucel T, or radionuclide therapy received in the castration-sensitive prostate cancer is NOT exclusionary if discontinued in the 28 days prior to Day 1 (Part 1) or randomization (Part 2).
- Treatment with any investigational agent within 4 weeks before Day 1 (Part 1) or randomization (Part 2).
- Prior treatment with opioids for pain related to either primary prostate cancer or metastasis within 28 days prior to Day 1 (Part 1) or randomization (Part 2).
- Current use of potent P-gp inhibitors within 7 days prior to Day 1 (Part 1) or randomization (Part 2).
- Major surgery (as defined by the investigator) within 2 weeks before Day 1 (Part 1) or randomization (Part 2), or palliative localized radiation therapy within 3 weeks before randomization (Part 2).
- Clinically significant cardiovascular disease
- Significant renal dysfunction as defined by any of the following laboratory abnormalities:
- Renal: eGFR < 30 mL/min/1.73 m2 by the MDRD equation (available via www.mdrd.com).
- Patients enrolled in Part 1 only: Moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) at screening.
- Significant hepatic dysfunction as defined by any of the following laboratory abnormalities on screening labs:
- Total serum bilirubin >1.5 times the upper limit of normal (ULN) (>3 × ULN for patients with documented 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 (>5 × ULN if liver function abnormalities are due to hepatic metastasis).
- Albumin <2.8 g/dL
- Absolute neutrophil count < 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 values at screening).
- Known or suspected brain metastasis or active leptomeningeal disease.
- Symptomatic or impending spinal cord compression or cauda equina syndrome.
- Any history of myelodysplastic syndrome, acute myeloid leukemia, or prior malignancy except for the following:
- Carcinoma in situ or non melanoma skin cancer
- A cancer diagnosed and treated = 5 years before randomization with no subsequent evidence of recurrence
- 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.
- Fertile male subjects who are unwilling or unable to use highly effective methods of contraception for the duration of the study and for 4 months after the last dose of investigational product.
- 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.
- Other acute or chronic medical (concurrent disease, infection, or comorbidity) or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that interferes with ability to participate in the study, 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.
- History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke, significant brain trauma). Also, history of loss of consciousness or transient ischemic attack within 12 months of randomization (Part 2).
- Disease progression during platinum chemotherapy or platinum therapy within 6 months (from the last dose) before day 1 (part 1) or randomization (part 2). Previous docetaxel therapy for mCSPC was allowed if it was more than 4 weeks after the last dose of docetaxel.
- If cytotoxic chemotherapy (including but not limited to docetaxel), biotherapeutics including cipruse-T or radionuclide therapy for castration-sensitive prostate cancer has been used, but on day (Part 1) or 28 days before randomization (Part 2), it is not excluded. If mCSPC has been treated with endocrine therapy (eg, bicalutamide, nilumitide, flutamide, estrogen, 5a-reductase inhibitors) but the drug is discontinued before randomization, this is not ruled out. * Exclude patients with corticosteroid dosages> 10 mg / day. (If clinically life-threatening conditions are indicated, simultaneous administration of systemic glucocorticoids, such as impact dose glucocorticoids) is permitted.
- Opioids were used to treat pain associated with primary prostate cancer or metastases on day 1 (part 1) or 28 days before randomization (part 2).
- Use a potent P-gp inhibitor within 7 days before Day 1 [Part 1] or randomization [Part 2]. List of potent P-gp inhibitors and other drugs that have been excluded due to interaction with Talazoparib or enzalutamide.
- Clinically significant cardiovascular disease, including any of the following: Myocardial infarction or symptomatic myocardial ischemia within 6 months before day 1 (part 1) or randomization (part 2). New York Heart Association Class III or IV congestive heart failure. Clinically significant ventricular arrhythmias (eg, persistent ventricular tachycardia, ventricular fibrillation, apical torsional ventricular tachycardia) have occurred within 1 year before screening. Mohs Type II or II heart block has occurred unless a permanent pacemaker has been implanted. Low blood pressure, manifested as systolic blood pressure <86 mm Hg at screening. Bradycardia, manifested as an electrocardiogram showing a heart rate <45 beats / minute at screening. Uncontrolled hypertension is present with systolic blood pressure> 170 mm Hg or diastolic blood pressure> 105 mm Hg at screening. However, after blood pressure is adequately controlled, patients can be screened a second time.
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