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Prostate Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Malcolm Mason, Howard Kynaston
The next era in the development of novel treatments for prostate cancer will surely be marked by biologically targeted agents. One such agent, the PARP inhibitor olaparib, has already been shown to yield responses in CRPC, particularly in disease characterized by defects in DNA repair.69
Ovarian and fallopian tube cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Andrew R. Clamp, Gordon C. Jayson
Initial clinical trials of olaparib, an oral PARP inhibitor focussed on women with germline BRCA mutations and recurrent ovarian cancer and have documented impressive response rates of up to 40% associated with clinical benefit.33,102,103 Subsequently, eligibility criteria have been broadened to include women with recurrent sporadic HGSOC in phase II studies. The use of maintenance olaparib, after response to platinum chemotherapy in this setting, dramatically increased PFS (HR – 0.35) compared to placebo and was well-tolerated with mild gastrointestinal side effects and fatigue most commonly reported. Much of this benefit was confined to the patients subsequently shown to carry germline or somatic BRCA mutations.104 Although no OS benefit has yet been reported, some patients have had very durable remissions. The combination of PARP inhibitors with chemotherapy increases myelotoxicity and so further trials will be concentrated on use in the maintenance setting. A key goal of these studies is to identify a predictive biomarker of HRD in addition to germline BRCA mutation to select patients most likely to gain benefit.
Efficacy and safety of olaparib in advanced ovarian cancer: a meta-analysis
Published in Journal of Obstetrics and Gynaecology, 2023
Yuanyuan Yang, Xiaoyun Yang, Huaifang Li, Xiaowen Tong, Xinxian Zhu
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a type of anticancer treatment that target cells deficient in homologous recombination repair (HRR), causing cell death via apoptosis once the DNA repair pathway is suppressed (Patel et al. 2011, Zheng et al. 2020). Olaparib is an effective, orally accessible PARPi that targets PARP-1, −2, and −3 in cells with a homologous recombination deficit, including those with BRCA1/2 mutations, to mediate this synthetic lethality (Guo et al. 2018). As an important new anticancer drug, olaparib has been used for the treatment of OC, gastric cancer, and other cancers (Robson 2017; Bang et al. 2017, Pujade-Lauraine et al. 2017). Olaparib maintenance therapy for advanced OC has been shown to reduce tumour size, prolong progression-free survival (PFS), and improve objective response rates (Ledermann et al. 2014, Oza et al. 2015, Moore et al. 2018). It is important to summarise these results to provide clinicians with an evidence-based reference. Therefore, we performed a meta-analysis of all published randomised controlled trials (RCTs) to evaluate the efficacy and safety of olaparib in advanced OC.
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
These investigators subsequently expanded the study to a randomized phase II portion, termed the TOPARP-B trial [29]. In this portion of the study, men were first screened for the presence of a potential sensitizing gene alterations for PARP inhibition and only those men with these underlying mutations were treated (i.e. only a biomarker-positive population). For this study, the included genes were: BRCA1, BRCA2, ATM, CDK12, PALB2, ARID1A, ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, MSH2, NBN, RAD50, and WRN. Patients were randomized to either 300 mg or 400 mg doses of olaparib, given orally twice daily. Ninety-eight men were treated, and the most commonly mutated genes were BRCA2 (n = 30), ATM (n = 21), and CDK12 (n = 21). Using the same composite overall response criteria as in the TOPARP-A study, 47% (43 of 92) of men had a response to olaparib, which included 34% by PSA50 criteria and 20% by RECIST 1.1 criteria. However, the responses varied by gene subgroup, with the highest rates of response being in those with BRCA1 or BRCA2 alterations (83%). Median radiographic progression-free survival also varied by subgroup, with the best outcomes reported in the BRCA1 or BRCA2 group at 8.3 months. Overall, the TOPARP-B studied confirmed the activity of olaparib in men with prostate cancer and importantly demonstrated that the underlying biology of the tumor is predictive of response.
Overview of Olaparib as a treatment option for metastatic castration-resistant prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Panagiotis Mourmouris, Athanasios Papatsoris, Athanasios Dellis, Iraklis Mitsogiannis, Mohamed Abou Chakra, Mohamad Moussa
Every day, different factors assault cell DNA and produce a wide variety of damages in it. The most common of these damages are the single strand breaks (SSBs) and the double strand breaks (DSBs) [1]. The above-mentioned damages could result in gene instability and therefore developing of cancer if the cell did not have repairing mechanisms. These mechanisms are following specific pathways: SSBs are following the base excision repair (BER) mechanism and the DSBs the homologous recombination (HR) mechanism [2]. Targeting these pathways can potentially provide therapeutic advantages for patients that have compromised repairing capabilities. Olaparib interferes with the BER pathway mainly due to selective inhibition of Poly ADP-ribose polymerase (PARP) 1 and 2 [3]. Furthermore, Olaparib can also being utilized as a adjunctive therapy in combination with chemotherapy (augmentation of chemotherapy cytotoxicity) or radiotherapy due to its capability of preventing PARP mediated DNA repair [4]. Olaparib has been utilized successfully for metastatic cancer of breast, ovaries, and pancreas [5–7] but it is relatively novel for the management of prostatic cancer.