Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050, Bruxelles, Belgium
Pharmacotherapeutic group: other antineoplastic agents
ATC code: L01XX60
Talazoparib is an inhibitor of PARP enzymes, PARP1, and PARP2. PARP enzymes are involved in cellular DNA damage response signalling pathways such as DNA repair, gene transcription, and cell death. PARP inhibitors (PARPi) exert cytotoxic effects on cancer cells by 2 mechanisms, inhibition of PARP catalytic activity and by PARP trapping, whereby PARP protein bound to a PARPi does not readily dissociate from a DNA lesion, thus preventing DNA repair, replication, and transcription, thereby resulting in apoptosis and/or cell death. Treatment of cancer cell lines that are harbouring defects in DNA repair genes with talazoparib single agent leads to increased levels of γH2AX, a marker of double stranded DNA breaks, and results in decreased cell proliferation and increased apoptosis. Talazoparib anti-tumour activity was also observed in a patient-derived xenograft (PDX) BRCA mutant breast cancer model where the patient was previously treated with a platinum-based regimen. In this PDX model talazoparib decreased tumour growth and increased γH2AX level and apoptosis in the tumours.
The effect of talazoparib on cardiac repolarisation was evaluated using time-matched electrocardiograms (ECGs) in assessing the relationship between the change of the QT interval corrected for heart rate (QTc) from baseline and the corresponding plasma talazoparib concentrations in 37 patients with advanced solid tumours. Talazoparib did not have a clinically relevant effect on QTc prolongation at the maximum clinically recommended dose of 1 mg once daily.
EMBRACA was an open-label, randomised, parallel, 2-arm multicentre study of Talzenna versus chemotherapy (capecitabine, eribulin, gemcitabine, vinorelbine) in patients with germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer who 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 setting. 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 randomised in the EMBRACA study, 408 (95%) were centrally confirmed to have a deleterious or suspected deleterious gBRCAm using a clinical trial assay; out of which 354 (82%) were confirmed using the BRACAnalysis CDx. BRCA mutation status (breast cancer susceptibility gene 1 [BRCA1] positive or breast cancer susceptibility gene 2 [BRCA2] positive) was similar across both treatment arms.
A total of 431 patients were randomised 2:1 to receive Talzenna 1 mg capsules once daily or chemotherapy at standard doses until progression or unacceptable toxicity. Of the 431 patients randomised onto EMBRACA, 287 were randomised to the Talzenna arm and 144 to the chemotherapy arm. Randomisation was 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 history of central nervous system metastasis (yes versus no).
Patient demographic, baseline, and disease characteristics were generally similar between the study treatment arms (see Table 4).
Table 4. Demographic, baseline, and disease characteristics – EMBRACA study:
| Talazoparib (N=287) | Chemotherapy (N=144) | |
|---|---|---|
| Median age (y [range]) | 45.0 (27.0, 84.0) | 50.0 (24.0, 88.0) |
| Age category (y), n (%) | ||
| <50 | 182 (63.4%) | 67 (46.5%) |
| 50 to <65 | 78 (27.2%) | 67 (46.5%) |
| ≥65 | 27 (9.4%) | 10 (6.9%) |
| Gender, n (%) | ||
| Female | 283 (98.6%) | 141 (97.9%) |
| Male | 4 (1.4%) | 3 (2.1%) |
| Race, n (%) | ||
| Asian | 31 (10.8%) | 16 (11.1%) |
| Black or African American | 12 (4.2%) | 1 (0.7%) |
| White | 192 (66.9%) | 108 (75.0%) |
| Other | 5 (1.7%) | 1 (0.7%) |
| Not reported | 47 (16.4%) | 18 (12.5%) |
| ECOG performance status, n (%) | ||
| 0 | 153 (53.3%) | 84 (58.3%) |
| 1 | 127 (44.3%) | 57 (39.6%) |
| 2 | 6 (2.1%) | 2 (1.4%) |
| Missing | 1 (0.3%) | 1 (0.7%) |
| Hormone receptor status, n (%) | ||
| HER2-positive | 0 (0.0%) | 0 (0.0%) |
| Triple-negative | 130 (45.3%) | 60 (41.7%) |
| Hormone receptor-positive (ER positive or PgR positive) | 157 (54.7%) | 84 (58.3%) |
| BRCA status by central or local laboratory assessment, n (%) | 287 (100.0%) | 144 (100.0%) |
| BRCA1-mutation positive | 133 (46.3%) | 63 (43.8%) |
| BRCA2-mutation positive | 154 (53.7%) | 81 (56.3%) |
| Time from initial diagnosis of breast cancer to diagnosis of advanced breast cancer (years) | ||
| n | 286 | 144 |
| Median | 1.9 | 2.7 |
| Minimum, maximum | 0, 22 | 0, 24 |
| Categories for time from initial diagnosis of breast cancer to diagnosis of advanced breast cancer | ||
| <12 months | 108 (37.6%) | 42 (29.2%) |
| ≥12 months | 178 (62.0%) | 102 (70.8%) |
| Number of prior cytotoxic regimens for locally advanced or metastatic disease | ||
| Mean (Std Dev) | 0.9 (1.01) | 0.9 (0.89) |
| Median | 1 | 1 |
| Minimum, maximum | 0, 4 | 0, 3 |
| Number of patients who received prior cytotoxic regimens for locally advanced or metastatic disease, n (%) | ||
| 0 | 111 (38.7%) | 54 (37.5%) |
| 1 | 107 (37.3%) | 54 (37.5%) |
| 2 | 57 (19.9%) | 28 (19.4%) |
| 3 | 11 (3.8%) | 8 (5.6%) |
| ≥4 | 1 (0.3%) | 0 (0.0%) |
| Number of patients who received following prior therapies, n (%) | ||
| Taxane | 262 (91.3%) | 130 (90.3%) |
| Anthracycline | 243 (84.7%) | 115 (79.9%) |
| Platinum | 46 (16.0%) | 30 (20.8%) |
Abbreviations: BRCA=breast cancer susceptibility gene; ER=estrogen receptor; HER2=human epidermal growth factor receptor 2; N=number of patients; n=number of patients in category; PgR=progesterone receptor.
The primary efficacy endpoint 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). The secondary objectives were objective response rate (ORR), overall survival (OS), safety, and PK.
The study demonstrated a statistically significant improvement in PFS for Talzenna compared with chemotherapy (see Table 5). The OS interim analysis was performed at 51% for the total number of planned events. Efficacy data for EMBRACA based on the primary analysis as assessed by the independent review and investigator are summarised in Table 5. The Kaplan-Meier curves for PFS is displayed in Figure 1.
Table 5. Summary of efficacy results – EMBRACA study:
| Talazoparib | Chemotherapy | |
|---|---|---|
| Progression-free survival by BICR | N=287 | N=144 |
| Events, number (%) | 186 (65%) | 83 (58%) |
| Median (95% CI), months | 8.6 (7.2, 9.3) | 5.6 (4.2, 6.7) |
| Hazard ratioa (95% CI) | 0.54 (0.41, 0.71) | |
| 2-sided p-valueb | p<0.0001 | |
| Overall survival (interim analysis)c | N=287 | N=144 |
| Events, number (%) | 108 (38%) | 55 (38%) |
| Median (95% CI), months | 22.3 (18.1, 26.2) | 19.5 (16.3, 22.4) |
| Hazard ratio (95% CI) | 0.76 (0.55, 1.06) | |
| 2-sided p-valueb | p=0.1053 | |
| Objective response by investigatord,e | N=219 | N=114 |
| ORR (, 95 CI) | 62.6 (55.8, 69.0) | 27.2 (19.3, 36.3) |
| Odds ratio (95% CI) | 4.99 (2.93, 8.83) | |
| 2-sided p-valuef | p<0.0001 | |
| Duration of response by investigatord | N=137 | N=31 |
| Median (IQR), months | 5.4 (2.8, 11.2) | 3.1 (2.4, 6.7) |
Abbreviations: BICR=blinded independent central review; CI=confidence interval; CMH=Cochran-Mantel-Haenszel; CR=complete response; IQR=interquartile range; ITT=intent-to-treat; ORR=objective response rate; OS=overall survival; PR=partial response; RECIST 1.1=Response Evaluation Criteria in Solid Tumors version 1.1.
a Hazard ratio was based on stratified Cox regression model with treatment as the only covariate (stratification factors: number of prior cytotoxic chemotherapy regimens, triple-negative status, history of central nervous system metastasis) and was relative to overall chemotherapy with <1 favouring talazoparib.
b Stratified Log-rank test.
c 51% of the projected final number of OS events occurred (163 of 321 deaths).
d Conducted in ITT with measurable disease population who had an objective response. The complete response rate was 5.5% for talazoparib compared to 0% for the chemotherapy arm.
e Per RECIST 1.1, confirmation of CR/PR was not required.
f Stratified CMH test.
Figure 1. Kaplan-Meier curves of PFS – EMBRACA study:
A series of prespecified subgroup PFS analyses was performed based on prognostic factors and baseline characteristics to investigate the internal consistency of treatment effect. Consistent with the overall results, a reduction in the risk of disease progression or death in favour of the talazoparib arm was observed in all individual patient subgroups (Figure 2).
Figure 2. Forest plot of PFS analyses for key subgroups – EMBRACA study:
The European Medicines Agency has waived the obligation to submit the results of studies with talazoparib in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).
Talazoparib exposure generally increased proportionally with dose across the range of 0.025 mg to 2 mg after daily administration of multiple doses. Following repeated daily dosing of 1 mg talazoparib to patients, the geometric mean (% coefficient of variation [CV%]) area under the plasma concentration-time curve (AUC) and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was in the range of 126 (107) ng•hr/mL to 208 (37) ng•hr/mL and 11 (90) ng/mL to 19 (27) ng/mL, respectively. Following repeated daily dosing, plasma talazoparib concentrations reached steady-state within 2 to 3 weeks. The median accumulation ratio of talazoparib following repeated oral administration of 1 mg once daily was in the range of 2.3 to 5.2. Talazoparib is a substrate of P-gp and BCRP transporters.
Following oral administration of talazoparib, the median time to Cmax (Tmax) was generally between 1 to 2 hours after dosing. The absolute bioavailability study has not been conducted in humans. However, based on urinary excretion data the absolute bioavailability is at least 41% with fraction absorbed of at least 69% (see Elimination). No significant effect of acid-reducing agents on talazoparib exposure is expected, given sufficient solubility of talazoparib at all pHs between 1 and 6.8. Twenty-eight percent (28%) of the patients in the pivotal study were taking acid-reducing agents, mainly proton pump inhibitors.
Food intake decreased the rate but not the extent of talazoparib absorption. Following a single oral dose of talazoparib with high-fat, high-calorie food (approximately 827 calories, 57% fat), the mean Cmax of talazoparib was decreased by approximately 46%, the median Tmax was delayed from 1 to 4 hours, while the AUC inf was not affected. Based on these results, Talzenna can be administered with or without food (see section 4.2).
The population mean apparent volume of distribution (Vss/F) of talazoparib was 420 L. In vitro, talazoparib is approximately 74% bound to plasma proteins with no concentration dependence over the concentration range of 0.01 μM to 1 μM.
Talazoparib undergoes minimal hepatic metabolism in humans. Following oral administration of a single 1 mg dose of [14C]talazoparib to humans, no major circulating metabolites were identified in plasma, and talazoparib was the only circulating drug-derived entity identified. No metabolites that individually represented more than 10% of the administered dose were recovered in the urine or faeces.
In vitro, talazoparib was not an inhibitor of cytochrome (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 or inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.
In vitro, talazoparib did not inhibit any of the major intestinal, hepatic or renal membrane transporters (P-gp, BCRP, organic anion transporting polypeptide [OATP]1B1, OATP1B3, organic cationic transporter [OCT]1, OCT2, organic anion transporter [OAT]1, OAT3, bile salt export pump [BSEP], multidrug and toxin extrusion [MATE]1 and MATE2-K) at clinically relevant concentrations.
In vitro, talazoparib did not inhibit any of the major uridine-diphosphate glucuronosyltransferase (UGT) isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15) at clinically relevant concentrations.
Renal elimination of unchanged drug (passive filtration and active secretion) is the major route of talazoparib elimination. P-gp is likely involved in talazoparib active renal secretion. The mean (±standard deviation) terminal plasma half-life of talazoparib was 90 (±58) hours and the population mean (inter-subject variability) apparent oral clearance (CL/F) was 6.5 (31%) L/h in cancer patients. In 6 female patients given a single oral dose of [14C]talazoparib, a mean of 69% (±8.6%) and 20% (±5.5%) of the total administered radioactive dose was recovered in urine and faeces, respectively. Excretion of unchanged talazoparib in urine was the major route of elimination accounting for 55% of the administered dose, while unchanged talazoparib recovered in the faeces accounted for 14%.
A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of age (ranging from 18 to 88 years), sex (53 males and 437 females), and body weight (ranging from 35.7 kg to 162 kg) on the PK of talazoparib. The results have shown that age, sex, and body weight had no clinically relevant effect on the PK of talazoparib.
Based on a population PK analysis that included 490 patients, where 41 patients were Asian and 449 patients were Non-Asian (361 White, 16 Black, 9 Others, and 63 Not reported), talazoparib CL/F was higher in Asian patients compared to Non-Asian patients, leading to 19% lower exposure (AUC) in Asian patients.
Pharmacokinetics of talazoparib have not been evaluated in patients <18 years of age.
Based on a population PK analysis that included 490 patients, where 132 patients had mild renal impairment (60 mL/min≤ CrCL <90 mL/min), 33 patients had moderate renal impairment (30 mL/min≤ CrCL <60 mL/min), and 1 patient had severe renal impairment (CrCL <30 mL/min), talazoparib CL/F was decreased by 14% and 37% in patients with mild and moderate renal impairment, respectively, when compared to patients with normal renal function (CrCL ≥90 mL/min). Insufficient data are available to estimate the impact of severe renal impairment on talazoparib CL/F in this patient population. The PK of talazoparib have not been studied in patients requiring haemodialysis (see section 4.2).
Based on a population PK analysis that included 490 patients, where 118 patients had mild hepatic impairment (total bilirubin ≤1.0 × ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the PK of talazoparib. The PK of talazoparib have not been studied in patients with moderate (total bilirubin >1.5 to 3.0 × ULN and any AST) or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST) (see section 4.2).
Carcinogenicity studies have not been conducted with talazoparib.
Talazoparib was not mutagenic in a bacterial reverse mutation (Ames) test. Talazoparib was clastogenic in an in vitro chromosomal aberration assay in human peripheral blood lymphocytes and in an in vivo micronucleus assay in rats at exposures similar to clinically relevant doses. This clastogenicity is consistent with genomic instability resulting from the primary pharmacology of talazoparib, indicating the potential for genotoxicity in humans.
In repeat-dose toxicity studies in rats and in dogs, the main findings at subtherapeutic exposures included bone marrow hypocellularity with dose-dependent decrease in haematopoietic cells, depletion of lymphoid tissue in multiple organs and atrophy and/or degenerative changes in testes, epididymis and seminiferous tubules. Additional findings at higher exposures included dose-dependent increase in apoptosis/necrosis in the gastrointestinal (GI) tract, liver and ovary. Most of the histopathologic findings were generally reversible while the testes findings were partially reversible after 4 weeks of dosing cessation. These toxicity findings are consistent with the pharmacology of talazoparib and its tissue distribution pattern.
In an embryo-foetal development study in rats, talazoparib resulted in embryo-foetal death, foetal malformation (depressed eye bulge, small eye, split sternebrae, fused cervical vertebral arch) and structural variations in bones at a maternal systemic AUC24 exposure approximately 0.09-fold the relevant human exposure at the recommended dose.
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