TALZENNA- talazoparib_capsule, liquid filled
Function and Efficacy
Talazoparib is an inhibitor of PARP enzymes, including PARP1 and PARP2, which play a role in DNA repair. In vitro studies with cancer cell lines that harbored defects in DNA repair genes, including BRCA1 BRCA2 BRCA1 BRCA2 BRCA1 BRCA2 The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of TALZENNA have not been fully characterized. Cardiac Electrophysiology At a dose of 1 mg (the recommended dosage for treatment of breast cancer), TALZENNA had no large QTc prolongation (i. After administration of TALZENNA 1 mg orally once daily as a single agent (the recommended dosage for breast cancer), the mean [% coefficient of variation (CV%)] AUC and maximum observed plasma concentration (C max trough After administration of TALZENNA 0. 5 mg orally once daily (the recommended dosage for prostate cancer) in combination with enzalutamide, the mean (CV%) steady-state C trough The pharmacokinetics (PK) of talazoparib is linear from 0. 025 mg to 2 mg (2 times the recommended dose for breast cancer). The median accumulation ratio of talazoparib following 1 mg orally once daily is 2. Talazoparib plasma concentrations reached steady-state within 2 to 3 weeks when administered as a single agent and within 9 weeks when coadministered with enzalutamide. Absorption The median time to C max max Food Effect Following administration of a TALZENNA 1 mg dose soft gelatin capsule with high-fat, high-calorie food (approximately 800 to 1,000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), the mean steady-state C max max Distribution The mean apparent volume of distribution of talazoparib is 420 L. In vitro Elimination The mean terminal plasma half-life (+/-standard deviation) is 90 (+/-58) hours and the mean apparent oral clearance (inter-subject variability) is 6. 5 L/h (31%). Metabolism Talazoparib undergoes minimal hepatic metabolism. The identified metabolic pathways include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro-talazoparib, and glucuronide conjugation. Excretion Excretion of talazoparib in urine was the major route of elimination. Approximately 69% (55% unchanged) of the total administered radiolabeled dose of talazoparib was recovered in urine, and 20% (14% unchanged) was recovered in feces. Specific Populations Age (18 to 88 years), sex, race (361 White, 41 Asian, 16 Black, 9 Others, and 63 Not Reported), body weight (36 to 162 kg), and mild to severe hepatic impairment had no clinically significant effect on the PK of talazoparib. Patients with Renal Impairment Mild (eGFR 60 en dash 89 mL/min/1. 73 m 2 2 2 2 max Drug Interaction Studies Clinical Studies Effect of P-gp Inhibitors: Coadministration of a P-gp inhibitor (itraconazole) with a single 0. 5 mg dose of TALZENNA increased talazoparib AUC and C max Coadministration with other P-gp inhibitors (including azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin) had no clinically significant effect on talazoparib pharmacokinetics. Effect of P-gp Inducers: Coadministration of a P-gp inducer (rifampin) with a single 1 mg dose of TALZENNA increased talazoparib C max Effect of Acid-Reducing Agents: Coadministration of acid-reducing agents including proton pump inhibitors (PPI), histamine receptor 2 antagonists (H 2 Enzalutamide: In Vitro Studies Transporters: Talazoparib is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BSEP, MATE1, or MATE2-K. CYP Enzymes: Talazoparib is not an inducer of CYP1A2, CYP2B6, or CYP3A4.
Indication
TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for: Breast Cancer BRCA BRCA 1. 1 HRR Gene-Mutated mCRPC 1. 2 TALZENNA is indicated as a single agent for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene ( BRCA BRCA [see Dosage and Administration (2. 1) TALZENNA is indicated in combination with enzalutamide for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) [see Dosage and Administration (2.
Usage and Dosage
4 Breast Cancer 2. 5 HRR Gene-Mutated mCRPC 2. 3 Information on the FDA-approved tests for the detection of genetic mutations is available at http://www. gov/companiondiagnostics g BRCA Select patients for the treatment of advanced breast cancer with TALZENNA based on the presence of germline BRCA [see Indications and Usage (1. 1) Clinical Studies (14. 1) HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer Select patients for the treatment of HRR gene-mutated mCRPC with TALZENNA based on the presence of alterations in genes directly or indirectly involved in HRR (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C) [see Indications and Usage (1. 2) Clinical Studies (14. 2) An FDA-approved test for the detection of HRR gene mutations for use with TALZENNA is not currently available. The recommended dosage of TALZENNA is 1 mg taken orally once daily, until disease progression or unacceptable toxicity. The recommended dosage of TALZENNA is 0. 5 mg taken orally once daily in combination with enzalutamide until disease progression or unacceptable toxicity. Refer to the enzalutamide prescribing information for recommended enzalutamide dosing information. Patients receiving TALZENNA and enzalutamide should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Take TALZENNA with or without food. Swallow TALZENNA capsules whole. Do not open or dissolve. If a patient vomits or misses a dose of TALZENNA, instruct them to take the next prescribed dose at the usual time. To manage adverse reactions, consider interruption of treatment with or without dose reduction based on severity and clinical presentation. Recommended dose reductions are indicated in Table 1 and Table 2. Treatment with TALZENNA should be discontinued if more than three dose reductions are required. g BRCA Table 1. Dose Reduction Levels for Adverse Reactionsem dashBreast Cancer Dose Reductions Dose Level Recommended starting dose 1 mg once daily First dose reduction 0. 75 mg once daily Second dose reduction 0. 5 mg once daily Third dose reduction 0. 25 mg once daily HRR Gene-mutated mCRPC Table 2. Dose Reduction Levels for Adverse Reactionsem dashmCRPC Dose Reductions Dose Level Recommended starting dose 0. 5 mg once daily First dose reduction 0. 35 mg once daily Second dose reduction 0. 25 mg once daily Third dose reduction 0. 1 mg once daily Refer to the enzalutamide prescribing information for dose modifications for adverse reactions associated with enzalutamide. g BRCA Monitor complete blood counts monthly and as clinically indicated [see Warnings and Precautions (5. Dose Modification and Management for Adverse Reactions Adverse Reactions Withhold TALZENNA Until Levels Resolve to Resume TALZENNA Hemoglobin <8 g/dL >=9 g/dL Resume TALZENNA at a reduced dose Platelet count <50,000/muL >=75,000/muL Neutrophil count <1,000/muL >=1500/µL Non-hematologic Grade 3 or Grade 4 <=Grade 1 Consider resuming TALZENNA at a reduced dose or discontinue g BRCA The recommended dosage of TALZENNA for patients with moderate renal impairment (CLcr 30 - 59 mL/min) is 0. 75 mg taken orally once daily [see Use in Specific Populations (8. 7) The recommended dosage of TALZENNA for patients with severe renal impairment (CLcr 15 - 29 mL/min) is 0. 5 mg taken orally once daily [see Use in Specific Populations (8. 7) HRR Gene-mutated mCRPC The recommended dosage of TALZENNA for patients with moderate renal impairment (CLcr 30 - 59 mL/min) is 0. 35 mg taken orally once daily in combination with enzalutamide [see Use in Specific Populations (8. 25 mg taken orally once daily in combination with enzalutamide [see Use in Specific Populations (8. 7) g BRCA Avoid coadministration of TALZENNA with the following P-glycoprotein (P-gp) inhibitors: itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil. If coadministration of TALZENNA with these P-gp inhibitors cannot be avoided, reduce the dose of TALZENNA to 0. 75 mg taken orally once daily. When the P-gp inhibitor is discontinued, increase the dose of TALZENNA (after 3 en dash 5 half-lives of the P-gp inhibitor) to the dose of TALZENNA that was used before starting the P-gp inhibitor [see Drug Interactions (7. 1) Monitor for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with other P-gp inhibitors [see Dosage and Administration (2.
Label
Adverse Reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 2) Most common adverse reactions (>=20%) as a single agent, including laboratory abnormalities, are: 6. 1 Most common adverse reactions (>=10%) in combination with enzalutamide, including laboratory abnormalities, are: 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to single agent TALZENNA in solid tumor clinical studies, including 286 patients enrolled in EMBRACA trial and to TALZENNA 0. 5 mg daily in combination with enzalutamide in 511 patients enrolled in the TALAPRO-2 trial that included 197 patients with HRR gene-mutated mCRPC. g BRCA EMBRACA The safety of TALZENNA as a single agent was evaluated in g BRCA [see Clinical Studies (14. 1) Serious adverse reactions of TALZENNA occurred in 32% of patients. Serious adverse reactions reported in >2% of patients included anemia (6%) and pyrexia (2%). Fatal adverse reactions occurred in 1% of patients, including cerebral hemorrhage, liver disorder, veno-occlusive liver disease, and worsening neurological symptoms (1 patient each). Permanent discontinuation due to adverse reactions occurred in 5% of TALZENNA patients. Dosing interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving TALZENNA; dose reductions due to any cause occurred in 53% of TALZENNA patients. The most common (>=20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, neutrophils decreased, lymphocytes decreased, platelets decreased, fatigue, glucose increased, aspartate aminotransferase increased, alkaline phosphatase increased, alanine aminotransferase increased, calcium decreased, nausea, headache, vomiting, alopecia, diarrhea, and decreased appetite. Table 5 and Table 6 summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study. Adverse Reactions Graded according to NCI CTCAE 4. Abbreviation: N=number of patients. Adverse Reactions TALZENNA N=286 (%) Chemotherapy N=126 (%) Grades 1-4 Grade 3 Grade 4 Grades 1-4 Grade 3 Grade 4 General disorders and administration site conditions Fatigue Includes fatigue and asthenia. 62 3 0 50 5 0 Gastrointestinal disorders Nausea 49 0. 3 0 47 2 0 Vomiting 25 2 0 23 2 0 Diarrhea 22 1 0 26 6 0 Nervous system disorders Headache 33 2 0 22 1 0 Skin and subcutaneous tissue disorders Alopecia 25 0 0 28 0 0 Metabolism and nutrition disorders Decreased appetite 21 0. 3 0 22 1 0 Clinically relevant adverse reactions in <20% of patients who received TALZENNA included abdominal pain (19%), dizziness (17%), dysgeusia (10%), dyspepsia (10%), stomatitis (8%), and febrile neutropenia (0. Select Laboratory Abnormalities (>=25%) of Patients in EMBRACA Abbreviation: N=number of patients. TALZENNA N This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter. =286 (%) Chemotherapy N =126 (%) Parameter Grades 1-4 Grade 3 Grade 4 Grades 1-4 Grade 3 Grade 4 Hemoglobin decreased 90 39 0 77 6 0 Neutrophils decreased 68 17 3 70 21 17 Lymphocytes decreased 76 17 0. 8 Platelets decreased 55 11 4 29 2 0 Glucose increased This number represents non-fasting glucose. 54 2 0 51 2 0 Aspartate aminotransferase increased 37 2 0 48 3 0 Alkaline phosphatase increased 36 2 0 34 2 0 Alanine aminotransferase increased 33 1 0 37 2 0 Calcium decreased 28 1 0 16 0 0 HRR Gene-mutated mCRPC The safety of TALZENNA in combination with enzalutamide was evaluated in patients with HRR gene-mutated mCRPC enrolled in TALAPRO-2 [see Clinical Studies (14. 2) Serious adverse reactions of TALZENNA in combination with enzalutamide occurred in 30% of patients. Serious adverse reactions reported in >2% of patients included anemia (9%) and fracture (3%). Fatal adverse reactions occurred in 1. 5% of patients, including pneumonia, COVID infection, and sepsis (1 patient each). Permanent discontinuation of TALZENNA due to adverse reactions occurred in 10% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in permanent discontinuation of TALZENNA were anemia (4%), fatigue, bone fracture, ischemic heart disease, and spinal cord compression (1% each). Dosage interruption of TALZENNA due to adverse reactions occurred in 58% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in dose interruption of TALZENNA were anemia (42%), neutropenia (15%), and platelet count decreased (9%) and fatigue (5%). Dose reduction of TALZENNA due to adverse reactions occurred in 52% of patients treated in the TALZENNA with enzalutamide arm. The most common adverse reactions which resulted in dose reduction of TALZENNA were anemia (43%), neutrophil count decreased (15%), platelet count decreased (6%), and fatigue (4%). The most common adverse reactions (>=10%), including laboratory abnormalities, in patients who received TALZENNA with enzalutamide were hemoglobin decreased, neutrophils decreased, lymphocytes decreased, fatigue, platelets decreased, calcium decreased, nausea, decreased appetite, sodium decreased, phosphate decreased, fractures, magnesium decreased, dizziness, bilirubin increased, potassium decreased, and dysgeusia. Table 7 and Table 8 summarize the most common adverse reactions and laboratory abnormalities, respectively, in the TALAPRO-2 study. TALZENNA with Enzalutamide N=197 Placebo with Enzalutamide N=199 Grades 1-4 % Grade 3 % Grade 4 % Grades 1-4 % Grade 3 % Grade 4 % Fatigue Includes fatigue and asthenia. 49 4 0 40 1 0 Nausea 21 2 0 17 1 0. 5 Decreased appetite 20 1 0 14 1 1 Fractures Fractures include multiple similar terms. 14 3 0 10 1. 5 0 Dizziness Includes dizziness, dizziness postural, vertigo. 5 0 Dysgeusia Includes ageusia, anosmia, dysgeusia. 5 0 0 Clinically relevant adverse reactions in <10% of patients who received TALZENNA with enzalutamide included abdominal pain (9%), vomiting (9%), alopecia (7%), dyspepsia (4%), venous thromboembolism (3%) and stomatitis (2%). Select Laboratory Abnormalities (>=10%) That Worsened from Baseline in Patients Who Received TALZENNA in TALAPRO-2 Abbreviation: N=number of patients. Laboratory Abnormality TALZENNA with Enzalutamide N=197 The denominator used to calculate the rate varied from 198 to 199 in the placebo with enzalutamide arm based on the number of patients with a baseline value and at least one post-treatment value. Placebo with Enzalutamide N=199 Grades 1‑4 % Grade 3 % Grade 4 % Grades 1‑4 % Grade 3 % Grade 4 % Hemoglobin decreased 79 41 0 34 6 0 Neutrophils decreased 60 18 1 18 0 1 Lymphocytes decreased 58 13 0 36 7 0 Platelets decreased 45 6 3 8 0. 5 0 Calcium decreased 25 0 1 11 0 1 Sodium decreased 22 3 0 20 1. 5 0 Phosphate decreased 17 3 1 13 2 0 Magnesium decreased 14 0 1 12 0 0. 5 Bilirubin increased 11 0. 5 0 7 0 0 Potassium decreased 11 0 1 7 1 0.
Special Population Medication
Lactation 8. 2 Renal Impairment 2. 7 Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12. 1) (see Data The background risk of major birth defects and miscarriage for the indicated population is unknown. In the general U. population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development toxicity study, pregnant rats received oral doses of 0. 15 mg/kg/day talazoparib during the period of organogenesis. Talazoparib caused embryo-fetal death at doses >=0. 015 mg/kg/day (approximately 0. 24 times the AUC in patients at the recommended dose of 1 mg daily). A dose of 0. 015 mg/kg/day caused decreased fetal body weights and an increased incidence of fetal malformations (depressed eye bulge, small eye, split sternebra, and fused cervical vertebral arch) and structural variations including misshapen or incomplete ossification of the sternebra, skull, rib, and vertebra. Risk Summary There are no data on the presence of talazoparib in human milk, the effects of the drug on milk production, or the effects of the drug on the breastfed child. Because of the potential for serious adverse reactions in a breastfed child from talazoparib, advise lactating women not to breastfeed during treatment with TALZENNA and for 1 month after the last dose. TALZENNA can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8. 1) Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating TALZENNA treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of TALZENNA. Males Based on genotoxicity and animal reproduction studies, advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception during treatment with TALZENNA and for 4 months following the last dose [see Use in Specific Populations (8. 1) Nonclinical Toxicology (13. 1) Infertility Males Based on animal studies, TALZENNA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13. 1) The safety and effectiveness of TALZENNA have not been established in pediatric patients. In clinical trials of TALZENNA enrolling 494 patients with advanced solid tumors who received TALZENNA 1 mg daily as a single agent, 85 (17%) patients were >=65 years of age, and this included 19 (4%) patients who were >=75 years old. There were 5 patients >=85 years old. In the TALAPRO-2 trial, of 197 patients who received TALZENNA, 77% were >=65 years of age, while 30% were >=75 years of age. No overall differences in safety or effectiveness of TALZENNA were observed between these patients and younger patients. No dosage modification is recommended for patients with hepatic impairment [see Clinical Pharmacology (12. 3) Reduce the recommended dosage of TALZENNA in patients with moderate (CLcr 30 en dash 59 mL/min) and severe (CLcr 15 en dash 29 mL/min) renal impairment [see Dosage and Administration (2. 7) [see Dosage and Administration (2. 5) No dose adjustment is recommended for patients with mild renal impairment (CLcr 60 en dash 89 mL/min). TALZENNA has not been studied in patients requiring hemodialysis.
Drug Interactions
P-gp Inhibitors 2. 1 BCRP Inhibitors 7. 1 Effect of P-gp Inhibitors Breast Cancer Avoid coadministration of TALZENNA with the following P-gp inhibitors: itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil. If coadministration of TALZENNA with these P-gp inhibitors cannot be avoided, reduce the dose of TALZENNA [see Dosage and Administration (2. 7) [see Dosage and Administration (2. 7) Coadministration of TALZENNA with these P-gp inhibitors increased talazoparib concentrations [see Clinical Pharmacology (12. 3) Monitor for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with other P-gp inhibitors [see Dosage and Administration (2. 5) HRR Gene-mutated mCRPC The effect of coadministration of P-gp inhibitors on talazoparib exposure when TALZENNA is taken in combination with enzalutamide has not been studied. Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a P-gp inhibitor [see Dosage and Administration (2. 5) Effect of BCRP Inhibitors Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a BCRP inhibitor [see Dosage and Administration (2. 5) Coadministration of TALZENNA with BCRP inhibitors may increase talazoparib exposure [see Clinical Pharmacology (12.
Other Information
OVERDOSAGE
There is no specific treatment in the event of TALZENNA overdose, and symptoms of overdose have not been established. In the event of overdose, discontinue treatment with TALZENNA, consider gastric decontamination, follow general supportive measures, and treat symptomatically.
NONCLINICAL TOXICOLOGY
Carcinogenicity studies have not been conducted with talazoparib. Talazoparib was clastogenic in an in vitro chromosomal aberration assay in human peripheral blood lymphocytes and in an in vivo bone marrow micronucleus assay in rats. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of talazoparib, indicating the potential for genotoxicity in humans. Talazoparib was not mutagenic in a bacterial reverse mutation (Ames) test. Fertility studies in animals have not been conducted with talazoparib. In repeat-dose toxicity studies up to 3-months duration, talazoparib-related findings in the testis and epididymis at doses >=0. 04 mg/kg/day in rats and >=0. 01 mg/kg/day in dogs included decreased organ weights, luminal cellular debris, reduced sperm, and degeneration/atrophy. These doses in rats and dogs resulted in approximately 1. 0 times and 0. 2 times, respectively, the exposure (AUC) in humans at the recommended dose of 1 mg daily. Follicular atresia of the ovary was observed in rats at doses >=1 mg/kg/day talazoparib, approximately 9. 5 times the AUC in patients at the recommended dose of 1 mg daily.
CLINICAL STUDIES
EMBRACA (NCT01945775) was an open-label study in which patients (N=431) with g BRCA Patients received no more than 3 prior cytotoxic chemotherapy regimens for their metastatic or locally advanced disease. Patients were required to have received treatment with an anthracycline and/or a taxane (unless contraindicated) in the neoadjuvant, adjuvant, and/or metastatic treatment setting. First-line treatment for advanced or metastatic disease with no prior adjuvant chemotherapy was allowed if the investigator determined that 1 of the 4 chemotherapy choices in the control arm would be an appropriate treatment option for the patient. Patients with prior platinum therapy for advanced disease were required to have no evidence of disease progression during platinum therapy. No prior treatment with a PARP inhibitor was permitted. Of the 431 patients randomized in the EMBRACA study, 408 (95%) were centrally confirmed to have a deleterious or suspected deleterious g BRCA registered BRCA BRCA1 BRCA2 The median age of patients treated with TALZENNA was 46 years (range 28 to 84) and 51 years (range 24 to 89) among patients treated with chemotherapy. Among all randomized patients, 1% versus 2% were males, 67% versus 75% were White; 11% versus 11% were Asian, and 4% versus 1% were Black or African American in the TALZENNA and chemotherapy arms, respectively. Almost all patients (98%) in both arms had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Approximately 56% of patients had estrogen receptor-positive and/or progesterone receptor-positive disease; 44% of patients had triple-negative disease, and the proportions were balanced across both treatment arms. Fifteen percent (15%) of patients in the TALZENNA arm and 14% of patients in the chemotherapy arm had a history of CNS metastases. Ninety-one percent (91%) of patients in the TALZENNA arm had received prior taxane therapy, and 85% had received prior anthracycline therapy in any setting. Sixteen percent (16%) of patients in the TALZENNA arm and 21% of patients in the chemotherapy arm had received prior platinum treatment in any setting. The median number of prior cytotoxic regimens for patients with advanced breast cancer was one; 38% received no prior cytotoxic regimens for advanced or metastatic disease, 37% received one, 20% received two, and 5% received three or more prior cytotoxic regimens. The major efficacy outcome measure was progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1. 1, as assessed by blinded independent central review (BICR). A statistically significant improvement in PFS was demonstrated for TALZENNA compared with chemotherapy. A sensitivity analysis of investigator-assessed PFS was consistent with the BICR-assessed PFS results. Consistent PFS results were observed across patient subgroups defined by study stratification factors (prior lines of chemotherapy, TNBC status, and history of CNS metastases). Efficacy data from the EMBRACA study are summarized in Table 9, and the Kaplan-Meier curves for PFS are shown in Figure 1 and final overall survival (OS) in Figure 2. Summary of Efficacy Results-EMBRACA Study Abbreviations: BICR=blinded independent central review; CI=confidence interval; DOR=duration of response; ITT=intent-to-treat; N=number of patients; ORR=objective response rate; OS=overall survival; PFS=progression-free survival. TALZENNA Chemotherapy PFS by BICR N=287 N=144 Disease progression or deaths, n (%) 186 (65) 83 (58) Median months (95% CI) 8. 7) Hazard ratio (95% CI) Hazard ratio is estimated from a Cox proportional hazards model stratified by prior use of chemotherapy for metastatic disease (0 versus 1, 2, or 3), by triple-negative disease status (triple-negative breast cancer [TNBC] versus non TNBC), and by history of central nervous system metastasis (yes versus no) and was relative to overall chemotherapy with <1 favoring talazoparib. 71) p-value P-values (2-sided) from the log-rank test stratified by number of prior cytotoxic chemotherapy regimens, triple negative status and history of central nervous system metastasis. 0001 Patients with measurable disease by investigator Conducted in ITT population with measurable disease at baseline. N=219 N=114 ORR, % (95% CI) Response rate based on confirmed responses. 8) Median Median estimated from Kaplan-Meier probabilities. 6) OS N=287 N=144 Deaths, n (%) 216 (75) 108 (75) Median months (95% CI) 19. 4) Hazard ratio (95% CI) 0. 07) p-value p=0. 1693 Figure 1. Kaplan-Meier Curves of PFS en dash EMBRACA Study Abbreviation: PFS=progression-free survival. Kaplan-Meier Curves of OS en dash EMBRACA Study (ITT Population) Abbreviations: ITT=intent-to-treat; OS=overall survival. Figure 1 Figure 2 The efficacy of TALZENNA in combination with enzalutamide was evaluated in TALAPRO-2 (NCT03395197), a randomized, double-blind, placebo-controlled, multi-cohort trial in which 399 patients with HRR gene-mutated (HRRm) mCRPC were randomized 1:1 to receive enzalutamide 160 mg daily plus either TALZENNA 0. 5 mg or placebo daily until unacceptable toxicity or progression. All patients received a GnRH analog or had prior bilateral orchiectomy and needed to have progressed on prior androgen deprivation therapy. Prior treatment with a CYP17 inhibitor or docetaxel for metastatic castration-sensitive prostate cancer (mCSPC) was permitted. Mutation status of HRR genes was determined prospectively using solid tumor tissue or circulating tumor DNA (ctDNA)-based next generation sequencing assays. Patients were required to have a mutation in at least one of 12 genes involved directly or indirectly in the HRR pathway ( ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C Randomization was stratified by previous treatment with a CYP17 inhibitor or docetaxel (yes/no). The median age was 70 years (range: 41 to 90); 100% were male; 68% were White, 21% Asian, 2. 8% Black, 0. 8% Other, 7% unknown/not reported; 12% were Hispanic/Latino; and baseline ECOG performance status was 0 (62%) or 1 (38%). Thirty-nine percent of patients had bone-only disease; 15% had visceral disease. In the mCSPC setting, 29% percent of patients had received docetaxel and 9% had received a prior CYP17 inhibitor. The most commonly mutated HRR genes (>5%), including co-occurring mutations, were: BRCA2 ATM CDK12 CHEK2 BRCA1 The major efficacy outcome measure was radiographic progression-free survival (rPFS) evaluated according to RECIST, version 1. 1 and Prostate Cancer Working Group (PCWG3) (bone) criteria, assessed by BICR. An additional efficacy outcome measure was OS. A statistically significant improvement in rPFS was demonstrated at the pre-specified interim analysis in patients randomized to TALZENNA in combination with enzalutamide compared with placebo in combination with enzalutamide. Consistent rPFS results were observed in patients who received or did not receive a prior CYP17 inhibitor or docetaxel. The OS data were not mature at the time of the rPFS analysis (24% of patients had died). Efficacy results are presented in Table 10 and Figure 3. Efficacy Results for TALAPRO-2 (HRR Gene-mutated mCRPC) Abbreviations: BICR=blinded independent central review; CI=confidence interval; CSPC=castration-sensitive prostate cancer; HRRm=homologous recombination repair gene-mutated; mCRPC=metastatic castration-resistant prostate cancer; N=number of patients; NE=not evaluable. TALZENNA with Enzalutamide (N=200) Placebo with Enzalutamide (N=199) Radiographic Progression-free Survival (rPFS) by BICR Number of rPFS events, n (%) 66 (33) 104 (52) Median months (95% CI) NE (21. 7) Hazard ratio (95% CI) Hazard ratio and CI were based on Cox PH model stratified by previous treatment for CSPC. 61) p-value p-value was based on log-rank test stratified by previous treatment for CSPC and compared with the boundary 0. 0001 Figure 3. Kaplan-Meier Curve for rPFS in TALAPRO-2 (HRR Gene-mutated mCRPC) Abbreviations: HRRm=homologous recombination repair gene-mutated; mCRPC=metastatic castration-resistant prostate cancer; rPFS=radiographic progression-free survival. Exploratory subgroup analyses of rPFS for patients with BRCA BRCA BRCA Table 11. Exploratory rPFS Subgroup Analyses by BRCA Abbreviations: BRCA BRCA Non- BRCA Includes 4 patients who were incorrectly randomized in the HRRm stratum who did not have HRR gene mutations. TALZENNA with Enzalutamide N=71 Placebo with Enzalutamide N=84 TALZENNA with Enzalutamide N=129 Placebo with Enzalutamide N=115 rPFS Number of events, n (%) 15 (21) 54 (64) 51 (40) 50 (43) Median months (95% CI) NE (NE, NE) 11. 7) Hazard ratio (95% CI) 0. 07) Figure 3.