bmn-673 and Anemia

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Health Organization International Clinical Trials Registry Platform, and international registers for published and unpublished double-blind randomized controlled trials from database inception to July 20, 2019.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

Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC).. TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing.. Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group.. Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations.. Pfizer.

Topics: Adolescent; Androgen Antagonists; Anemia; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

The phase II TALAPRO-1 study (NCT03148795) demonstrated durable antitumor activity in men with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). Here, we detail the safety profile of talazoparib.. Men received talazoparib 1 mg/day (moderate renal impairment 0.75 mg/day) orally until radiographic progression, unacceptable toxicity, investigator decision, consent withdrawal, or death. Adverse events (AEs) were evaluated: incidence, severity, timing, duration, potential overlap of selected AEs, dose modifications/discontinuations due to AEs, and new clinically significant changes in laboratory values and vital signs.. In the safety population (N = 127; median age 69.0 years), 95.3% (121/127) experienced all-cause treatment-emergent adverse events (TEAEs). Most common were anemia (48.8% [62/127]), nausea (33.1% [42/127]), decreased appetite (28.3% [36/127]), and asthenia (23.6% [30/127]). Nonhematologic TEAEs were generally grades 1 and 2. No grade 5 TEAEs or deaths were treatment-related. Hematologic TEAEs typically occurred during the first 4-5 months of treatment. The median duration of grade 3-4 anemia, neutropenia, and thrombocytopenia was limited to 7-12 days. No grade 4 events of anemia or neutropenia occurred. Neither BRCA status nor alteration origin significantly impacted the safety profile. The median (range) treatment duration was 6.1 (0.4-24.9) months; treatment duration did not impact the incidence of anemia. Only 3 of the 15 (11.8% [15/127]) permanent treatment discontinuations were due to hematologic TEAEs (thrombocytopenia 1.6% [2/127]; leukopenia 0.8% [1/127]).. Common TEAEs associated with talazoparib could be managed through dose modifications/supportive care. Demonstrated efficacy and a manageable safety profile support continued evaluation of talazoparib in mCRPC.. NCT03148795.

Topics: Aged; Anemia; Antineoplastic Agents; DNA Damage; Humans; Male; Neutropenia; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant

Poly(ADP-ribose) polymerase inhibitors, such as talazoparib, may affect hematopoiesis. This analysis characterized the relationship between talazoparib exposure and the most common grade ≥ 3 hematopoietic adverse events (AEs) leading to dose modification in the phase 2 (ABRAZO) and phase 3 (EMBRACA) trials. The relationship between time-varying average talazoparib concentration (C

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Breast Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Dosage Calculations; Female; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Humans; Middle Aged; Mutation; Neutropenia; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Prognosis; Proportional Hazards Models; Thrombocytopenia