China
Africa
Explore chapters and articles related to this topic
Identifying Breast Cancer Treatment Biomarkers Using Transcriptomics
Published in Shazia Rashid, Ankur Saxena, Sabia Rashid, Latest Advances in Diagnosis and Treatment of Women-Associated Cancers, 2022
FDA has approved many NGS companion diagnostic tests for multiple cancers and biomarkers using liquid biopsies which are non-evasive like Foundation Medicine Inc.’s Liquid CDx test for detecting biomarkers using cell-free DNA isolated from plasma. Approved biomarker indicators include mutational profiling in BRCA1 and BRCA2, which the major known breast cancer risk genes. This test uses 324 gene panels and checks for copy number changes, gene fusions, tumour mutation burden, and changes in PDL-1 (IHC). Rucaparib (RUBRACA, Clovis Oncology, Inc.) is used to treat patients with ovarian cancers using BRCA1 and BRCA2. The PIK3CA gene is used for breast cancer detection with Alpelisib (PIQRAY, Novartis Pharmaceutical Corporation).
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 ARIEL2 study was an international, multicenter phase 2 trial evaluating the use of rucaparib in high-grade ovarian cancer. The study was conducted in two parts. In part 1, patients with platinum-sensitive high-grade recurrent ovarian cancer were classified into three predefined homologous recombination (HR) groups. These were BRCA mutant (germline or somatic), BRCA wild type with tumor genomic loss of heterozygosity (LOH)-high, and BRCA wild type with LOH-low. Patients were treated with oral rucaparib 600 mg twice daily. Interestingly, patients with both BRCA mutation (hazard ratio 0.27, 95% CI 0.16–0.44, p < 0.0001) and LOH-high (0.62, 0.42–0.90, p = 0.011) showed improved PFS when compared to patients with LOH-low. This study provided proof of the principle that in addition to BRCA mutation, the assessment of LOH could also be used to identify patients who would benefit from PARP inhibitors [118].
Pharmacologic Ascorbate Influences Multiple Cellular Pathways Preferentially in Cancer Cells
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Qi Chen, Kishore Polireddy, Ping Chen, Ramesh Balusu, Tao Wang, Ruochen Dong
Thus, pharmacologic ascorbate not only damages cancer cell DNA, but it also suppresses DNA repairing machinery. This makes it mechanistically plausible to combine ascorbate not only with DNA damaging chemotherapeutics (such as platinum-based drugs), but also with PARP inhibitor—one of the most exciting new classes of oncology drugs that has transformed the management of ovarian cancer. An early phase clinical trial in ovarian cancer patients combing high-dose intravenous ascorbate (IVC) and the standard carboplatin/paclitaxel proved the safety and feasibility, achieved improved toxicity profiles in the patients, and suggested prolonged disease progression-free survival (PFS) [4]. PARP inhibitors (such as olaparib, rucaparib, and niraparib) exhibit good efficacy and clinical benefits in women carrying BRCA1/2-mutated ovarian cancers. However, the majority of women who have ovarian or breast cancer (∼80%) do not have germline or somatic BRCA1/2 mutation, to whom PARP inhibitors alone have very limited efficacy. In a mouse model, adding pharmacologic ascorbate treatment significantly sensitized a BRCA1/2 wild-type ovarian cancer to olaparib treatment [22]. The combination treatment of ascorbate and PARP inhibitor provides a novel and promising therapeutic option for patients with cancers not responding to PARP inhibition alone, and it is worth clinical investigation. Such a strategy could be applied to a variety of heterogeneous and hard-to-treat malignancies, such as breast, pancreatic, and prostate cancers, where BRCA1, BRCA2 or other HR repair proteins are instrumental in the repair of DNA DSBs, and the potential of both PARP inhibitors and ascorbate has not been fully exploited.
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
Rucaparib is a PARP inhibitor with a slightly different metabolism and affinity for various PARP enzymes as compared to olaparib [43]. Rucaparib is metabolized by CYP2D6, CYP1A2, and CYP3A4; whereas olaparib is primarily metabolized by CYP3A4/5. Rucaparib is more selective for PARP1 and PARP2 compared to olaparib. Rucaparib has similarly been developed for use in various malignancies, including ovarian and prostate cancer. The TRITON2 study was a single-arm phase 2 trial that tested rucaparib in men with HRRd mCRPC. In the study, patients were required to have been previously treated with at least one novel ARSI and prior chemotherapy for mCRPC. A total of 115 patients were included who had BRCA1 or BRCA2 mutations, the majority (n = 102) of which were in BRCA2 [44]. Fifty-five percent of these patients had a confirmed PSA50 response, and 44% of patients with measurable disease had an objective radiographic response. The median time to PSA progression by prostate cancer working group 3 (PCWG3) criteria [45] was 6.5 months, and the median radiographic progression-free survival was 9.0 months. Based upon this response and survival data, the FDA granted accelerated approval to rucaparib for the treatment of patients with mCRPC harboring BRCA1 or BRCA2 mutations with prior treatment with a novel ARSI and chemotherapy [46]. The NCCN guidelines list rucaparib as a category 2A option for treatment of mCRPC with mutations in BRCA1 or BRCA2 after prior docetaxel and prior novel ARSI therapy [32].
Rucaparib: a new treatment option for ovarian cancer
Published in Expert Opinion on Pharmacotherapy, 2018
Ilaria Sabatucci, Giuseppa Maltese, Stefano Lepori, Elisa Tripodi, Giorgio Bogani, Domenica Lorusso
Ongoing clinical trials evaluating the role of rucaparib in the treatment of ovarian cancer are summarized in Table 1. The use of PARP inhibitors as a frontline maintenance therapy is of particular interest. This presents the same rationale as treatment at recurrence and allows some respite and possibly increases the time to subsequent treatment for advanced ovarian cancer patients. The MITO 25 trial is ongoing: the trial will evaluate the role of rucaparib either alone or in combination with Bevacizumab versus Bevacizumab as a maintenance treatment in patients with advanced ovarian cancer that does not progress after first-line platinum-based chemotherapy. The combination of rucaparib with immune checkpoint inhibitors is being explored in two ongoing trials in advanced ovarian cancer: the NCT03101280 trial is evaluating the combination of rucaparib and atezolizumab, an anti-PD-L1 monoclonal antibody, in recurrent platinum-sensitive ovarian cancer and triple-negative breast cancer, while the combination of rucaparib and nivolumab will be studied as a maintenance treatment in a randomized phase III trial of frontline therapy in patients with stage III-IV ovarian, primary peritoneal or fallopian tube cancer.
Rucaparib for the treatment of ovarian cancer
Published in Expert Opinion on Orphan Drugs, 2018
Sunu Lazar Cyriac, Katherine Karakasis, Amit M. Oza
In vitro results of inhibition of PARP by Rucaparib were reproduced in in vivo studies. Thomas et al. [41] did extensive in vitro analysis of 42 potent PARPi molecules. Seventeen of these were subsequently chosen for further in vivo experiments. Rucaparib (AG014699) was found to be 10 times more potent than the initial lead molecule AG14361, and so was chosen for further clinical trials [41]. Rucaparib showed excellent chemosensitization properties with Temozolomide as well as good radiosensitization potential. Drew et al. [44] conducted in vivo tests of Rucaparib (AG014699) in multiple cell line including, BRCA1/2 wild type, BRCA1-mutated, BRCA2-mutated, BRCA2 heterozygous and epigenetically silenced BRCA1, two Chinese hamster ovary cell lines, parental AA8, and XRCC3-mutated IRS 1SF cell lines. BRCA1/2-mutated cell lines and epigenetically silenced cell lines were more sensitive to Rucaparib as well as had more cytotoxicity toward Rucaparib [44].