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BRCA Mutation and PARP Inhibitors
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Arjun Mittra, James H. Doroshow, Alice P. Chen
The first-in-human clinical trial of talazoparib involved a phase 1 dose escalation cohort in patients with advanced malignancies. The subsequent expansion cohort included patients who were predicted to be sensitive to PARP inhibition. This included patients with germline BRCA1/2-mutated tumors, as well as triple-negative breast cancers, high-grade serous and/or undifferentiated ovarian, fallopian tube, or peritoneal cancers, and castration-resistant prostate and pancreatic cancers. Patients with Ewing sarcoma and small cell lung cancer were included based on preclinical data suggesting potential sensitivity to PARP inhibition. The most robust responses were seen in the BRCA1 /2-mutated breast and ovarian cancers. At the maximum tolerated dose of 1 mg daily, 7 of 14 patients with BRCA-mutated breast cancer achieved a response, with one complete response (CR); 5 of 12 patients with BRCA-mutated ovarian cancer achieved responses, including one CR. Amongst all the BRCA-mutated ovarian cancer patients treated at any dose level of talazoparib, there was an improved overall response rate in platinum-sensitive patients (55%), compared to platinum-resistant patients (20%) [26].
Breast Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Amy Case, Gwenllian Edwards, Catherine Pembroke
Inhibitors of poly ADP-ribose polymerase (PARP inhibitors) such as olaparib and talazoparib have certainly shown clinical benefits within the BRCA1/2 mutant population185,186 and continue to hold promise as treatments for the wider group of triple-negative cancers, but in early trials their benefits seem to be limited to BRCA-deficient cancers. Talazoparib was studied within the phase III EMRACA trial, comparing the PARP inhibitor against single-agent capecitabine, vinorelbine, eribulin, or gemcitabine in the metastatic setting. An improved PFS relative to chemotherapy (8.6 months versus 5.6 months, HR 0.64, 95%CI 0.41–0.71) was concluded in addition to reported improvements in quality of life as well as improved tolerance of the drug in the talazoparib arm.186
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Four PARP inhibitors reached the approval stage by the FDA and EMA between 2016 and 2019 (Figure 5.104). These are olaparib (LynparzaTM), developed by AstraZeneca and licensed for ovarian, fallopian tube, and peritoneal cancers (starting treatment no later than eight weeks after completion of a final dose of a platinum-containing regimen); talazoparib (AlzennaTM), developed by Pfizer and used for breast cancer; rucaparib (RubracaTM), developed by Clovis Oncology and used for ovarian, fallopian tube, and peritoneal cancers; and niraparib (ZejulaTM), developed by Tesaro and used for fallopian tube and peritoneal cancer. All of these agents are orally available and recommended for patients with mutated BRCA for which a pharmacogenomic test is available (see Chapter 11). A molecular model of olaparib binding to the NAD+-binding site of the PARP1 is shown in Figure 5.105. Structures of the approved PARP inhibitors olaparib (LynparzaTM), talazoparib (AlzennaTM), rucaparib (RubracaTM), and niraparib (ZejulaTM).Molecular model of the PARP inhibitor olaparib (dark grey) occupying the NAD+-binding site of the DNA-repair protein PARP-1 (From the PDB Database: Entry 5DS3).
The anti-tumor efficiency of low-dose apatinib-based chemotherapy in pretreated HER2-negative breast cancer with brain metastases
Published in Annals of Medicine, 2023
Xuelian Chen, Xue Bai, Xiaofeng Xie, Jiayi Huang, Liping Chen, Lin Song, Xiaofeng Lan, Qiuyi Zhang, Jinfeng Guo, Caiwen Du
The impassability of the BBB impedes the widespread use of many effective drugs. Small molecules such as TKIs, with favorable properties that allow them for a more efficient penetration through the BBB, are attractive candidates for BCBM. The most remarkable representative is that the addition of anti-HER2 TKI tucatinib to trastuzumab and chemotherapy in the HER2CLIMB trial doubled the intracranial ORR to 47.3% and obtained a median OS of 18.1 months [8]. For HER2-negative breast cancer, some small molecule compounds also exhibit special CNS activity. Talazoparib is a poly ADP-ribose polymerase (PARP) inhibitor that prevents double-stranded DNA repair in BRCA 1/2-mutated cancer. In phase III clinical study (EMBRACA), among 63 patients with BCBM and germline BRCA1/2 mutations [24], talazoparib significantly prolonged the median PFS compared with chemotherapy (HR = 0.32, 95% CI: 0.15 to 0.68), suggesting that talazoparib can effectively penetrate the BBB. The cyclin-dependent kinase (CDK) 4/6 inhibitor abemaciclib, is another small-molecule chemical which could achieve therapeutic concentrations in brain metastases tissues approximating that in plasma [25]. In a phase II trial focused on BCBM, abemaciclib obtained an intracranial CBR of 24% in heavily pretreated MBC patients [26].
The evolving landscape of PARP inhibitors in castration-resistant prostate cancer: a spotlight on treatment combinations
Published in Expert Review of Clinical Pharmacology, 2022
Benjamin A. Teply, Emmanuel S. Antonarakis
Talazoparib is another PARP inhibitor that has been investigated as a monotherapy in mCRPC. In the TALAPRO-1 study, eligible patients had mCRPC and were required to have tumors with HRRd, defined as an alteration in ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C [55]. Prior treatments that were mandated included at least one taxane chemotherapy and one novel ARSI. Patients were treated with oral talazoparib 1 mg daily. The primary outcome was objective response in patients with measurable disease. A total of 127 patients were treated, among which 104 had measurable disease for inclusion in the primary endpoint analysis. Among all patients, the objective response rate was 30%, however, the rates highly varied based upon the underlying gene mutation. For patients with BRCA1 or BRCA2 alterations, 28/61 had objective responses (46%), compared with only 12% (2/17) for ATM alteration; 25% (1/4) for PALB2 alterations; and 0% (0/22) for all others. Forty-six percent of patients had PSA50 responses, again mostly driven by the high rates in BRCA2-mutated cases. The median radiographic progression-free survival was an impressive 11.2 months for those with BRCA1 or BRCA2 alterations, and it was 5.6 months for the entire study population.
Development of the PARP inhibitor talazoparib for the treatment of advanced BRCA1 and BRCA2 mutated breast cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Evthokia A. Hobbs, Jennifer K. Litton, Timothy A. Yap
Across the available clinical trials, hematological toxicities have been identified as the main adverse events (AE). In a detailed separate safety analysis of the EMBRACA trial, the most common toxicity was hematologic (69%), which predominantly occurred in the first 3–4 months of treatment [103]. Grade 3–4 hematologic toxicity in the majority of patients was nevertheless short-lived, with a median time to recovery of 7–8 days with resolution through the use of blood transfusions and dose-modifications, which was similar to the standard-therapy group. Permanent discontinuation of talazoparib for hematologic toxicity was required in only <2% of patients and overlapping grade 3–4 hematologic events occurred in <6%. AEs associated with death occurred in 6 (2.1%) patients receiving talazoparib and 4 (3.2%) receiving standard treatment. Febrile neutropenia was rare and only occurred in one patient in each arm (<1%). Non-hematologic toxicities included fatigue, nausea/vomiting and alopecia that increased during the first 4 weeks then plateaued after week 50. Interestingly, grade 2 fatigue and asthenia were more common in talazoparib (24%) compared to the standard-therapy group (16%), however this was not reflected in the global health status and quality of life (GHS/QoL) assessment discussed in the section below. Overall, talazoparib side effects were well managed with supportive care and dose modifications.