bmn-673 and Neoplasm-Metastasis

Breast cancer is the most commonly diagnosed cancer and is the leading cause of cancer death in women worldwide. Both talazoparib and olaparib are approved by the US Food and Drug Administration for treating. To compare the efficacy, safety, and acceptability of single-agent poly (ADP-ribose) polymerase (PARP) inhibitors for patients with. We included two trials comprising 733 participants. Compared with talazoparib, olaparib was not associated with improved PFS (. Both talazoparib and olaparib have similar efficacy, safety, and acceptability in patients with. We performed a systematic review and network meta-analysis. We performed a systematic search of Web of Science, Embase, PubMed, Medline, ClinicalTrials.gov, the Cochrane Central Register of Controlled Trials, and the World Health Organization International Clinical Trials Registry Platform, and international registers for published and unpublished double-blind randomized controlled trials from database inception to July 20, 2019. The pooled estimates of hazard ratios (HR) with 95% credible intervals (CrIs) were calculated for PFS, OS, and the time to deterioration of quality of life (QoL). The pooled estimates of odds ratio (

Topics: Anemia; Breast Neoplasms; Female; Genes, BRCA1; Humans; Mutation; Neoplasm Metastasis; Network Meta-Analysis; Neutropenia; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Proportional Hazards Models; Quality of Life; Receptor, ErbB-2; Survival Rate; Treatment Outcome

PARP inhibitors in combination with androgen receptor-targeted therapy have demonstrated potential in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Here, we describe the design and rationale of the multinational, phase III, two-part TALAPRO-2 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide as a first-line treatment for patients with mCRPC with or without DNA damage response (DDR) alterations. This study has two co-primary end points: radiographic progression-free survival (rPFS) by blinded independent clinical review in all-comers (cohort 1) and in patients with DDR alterations (cohort 2). TALAPRO-2 will demonstrate whether talazoparib plus enzalutamide can significantly improve the efficacy of enzalutamide in terms of rPFS in both molecularly unselected and DDR-deficient patients with mCRPC (NCT03395197). Clinical Trial Registration: NCT03395197 (ClinicalTrials.gov).

Topics: Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Benzamides; DNA Damage; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant

Talazoparib is a poly(ADP-ribose) polymerase enzyme inhibitor. This open-label, non-randomized, phase 1 study of talazoparib investigated the safety, pharmacokinetics, and preliminary antitumor activity in Japanese patients with locally advanced or metastatic solid tumors, regardless of mutations in DNA damage repair-related genes, who are resistant to/ineligible for standard therapies.. Patients received talazoparib dosed orally at 0.75 or 1 mg once daily using a modified 3 + 3 dose-escalation scheme. Primary endpoint was dose-limiting toxicities during the first cycle of talazoparib.. Nine patients (median age 62.0 years) were included: 3 and 6 patients at the 0.75 and 1.0 mg once-daily dose levels, respectively. No dose-limiting toxicities were reported. The most commonly reported treatment-emergent adverse events (≥2 patients) were anemia, stomatitis, maculopapular rash, platelet count decreased, neutrophil count decreased, and alanine aminotransferase increased. Three patients had grade ≥ 3 treatment-emergent adverse events (anemia, brain metastases [1 patient each], and neutrophil and white blood cell count decreased [same patient]). Two patients temporarily discontinued treatment due to a treatment-emergent adverse event, and 1 patient required a dose reduction for neutrophil count decreased (all at 1 mg once daily). Talazoparib exposure (C. Single-agent talazoparib was well tolerated and had preliminary antitumor activity in Japanese patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT03343054 (November 17, 2017).

Topics: Adult; Aged; Antineoplastic Agents; Asian People; Dose-Response Relationship, Drug; Humans; Japan; Maximum Tolerated Dose; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasms; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors

Poly(ADP-ribose) polymerase (PARP) inhibitors have antitumour activity against metastatic castration-resistant prostate cancers with DNA damage response (DDR) alterations in genes involved directly or indirectly in homologous recombination repair (HRR). In this study, we assessed the PARP inhibitor talazoparib in metastatic castration-resistant prostate cancers with DDR-HRR alterations.. In this open-label, phase 2 trial (TALAPRO-1), participants were recruited from 43 hospitals, cancer centres, and medical centres in Australia, Austria, Belgium, Brazil, France, Germany, Hungary, Italy, the Netherlands, Poland, Spain, South Korea, the UK, and the USA. Patients were eligible if they were men aged 18 years or older with progressive, metastatic, castration-resistant prostate cancers of adenocarcinoma histology, measurable soft-tissue disease (per Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]), an Eastern Cooperative Oncology Group performance status of 0-2, DDR-HRR gene alterations reported to sensitise to PARP inhibitors (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), had received one or two taxane-based chemotherapy regimens for metastatic disease, and progressed on enzalutamide or abiraterone, or both, for metastatic castration-resistant prostate cancers. Eligible patients were given oral talazoparib (1 mg per day; or 0·75 mg per day in patients with moderate renal impairment) until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or death. The primary endpoint was confirmed objective response rate, defined as best overall soft-tissue response of complete or partial response per RECIST 1.1, by blinded independent central review. The primary endpoint was assessed in patients who received study drug, had measurable soft-tissue disease, and had a gene alteration in one of the predefined DDR-HRR genes. Safety was assessed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, NCT03148795, and is ongoing.. Between Oct 18, 2017, and March 20, 2020, 128 patients were enrolled, of whom 127 received at least one dose of talazoparib (safety population) and 104 had measurable soft-tissue disease (antitumour activity population). Data cutoff for this analysis was Sept 4, 2020. After a median follow-up of 16·4 months (IQR 11·1-22·1), the objective response rate was 29·8% (31 of 104 patients; 95% CI 21·2-39·6). The most common grade 3-4 treatment-emergent adverse events were anaemia (39 [31%] of 127 patients), thrombocytopenia (11 [9%]), and neutropenia (ten [8%]). Serious treatment-emergent adverse events were reported in 43 (34%) patients. There were no treatment-related deaths.. Talazoparib showed durable antitumour activity in men with advanced metastatic castration-resistant prostate cancers with DDR-HRR gene alterations who had been heavily pretreated. The favourable benefit-risk profile supports the study of talazoparib in larger, randomised clinical trials, including in patients with non-BRCA alterations.. Pfizer/Medivation.

Topics: Aged; Antineoplastic Agents; DNA Repair; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Response Evaluation Criteria in Solid Tumors; Survival Analysis

To assess talazoparib activity in germline. ABRAZO (NCT02034916) was a two-cohort, two-stage, phase II study of talazoparib (1 mg/day) in germline. We enrolled 84 patients (cohort 1,. Talazoparib exhibited promising antitumor activity in patients with advanced breast cancer and germline

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Cohort Studies; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Germ-Line Mutation; Humans; Middle Aged; Neoplasm Metastasis; Phthalazines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Salvage Therapy