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The New England Journal of Medicine Mar 2021
Topics: Humans; Male; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant
PubMed: 33761221
DOI: 10.1056/NEJMc2100225 -
The New England Journal of Medicine Mar 2021
Topics: Humans; Male; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant
PubMed: 33761222
DOI: 10.1056/NEJMc2100225 -
BioDrugs : Clinical Immunotherapeutics,... Apr 2015Olaparib (Lynparza™) is a first-in-class, orally-active, small molecule, poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in homozygous... (Review)
Review
Olaparib (Lynparza™) is a first-in-class, orally-active, small molecule, poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. In the EU, the capsule formulation of olaparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive, relapsed, BRCA-mutated (germline and/or somatic), high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. This approval was based on the results of study 19, a randomized phase II trial in 265 patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer (HGSOC) who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Study 19 met its primary endpoint by demonstrating a significant improvement in progression-free survival in patients receiving olaparib compared with those receiving placebo. Moreover, a preplanned retrospective analysis identified those patients with a BRCA mutation (who comprised one-half of the overall study population) as being the subgroup that derived the greatest clinical benefit from olaparib. Single-agent olaparib was generally well tolerated, with the majority of adverse events being of mild to moderate severity and not requiring interruption of treatment. Fatigue, anaemia and neutropenia were the most frequently reported severe (grade ≥3) adverse events. An as yet unapproved tablet formulation of olaparib that has a lower pill burden than the capsule formulation is currently being investigated in phase III clinical studies.
Topics: Antineoplastic Agents; Disease-Free Survival; Female; Humans; Maintenance Chemotherapy; Ovarian Neoplasms; Phthalazines; Piperazines
PubMed: 25899311
DOI: 10.1007/s40259-015-0125-6 -
Bulletin Du Cancer Sep 2019
Topics: Adenocarcinoma; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Genes, BRCA1; Genes, BRCA2; Germ-Line Mutation; Humans; Pancreatic Neoplasms; Phthalazines; Piperazines; Placebos; Progression-Free Survival; Randomized Controlled Trials as Topic
PubMed: 31399206
DOI: 10.1016/j.bulcan.2019.07.002 -
Supportive Care in Cancer : Official... Jun 2022This qualitative study sought to learn patients' perspectives on olaparib - including maintenance olaparib - in their own words.
PURPOSE
This qualitative study sought to learn patients' perspectives on olaparib - including maintenance olaparib - in their own words.
METHODS
Olaparib-treated patients were interviewed by phone. A semi-structured interview guide that focused on symptoms and quality of life was formulated in alignment with the study objective. Interviews were transcribed and analyzed with content analysis.
RESULTS
Twenty olaparib-treated patients were interviewed. Four themes emerged: (1) The Long Cancer Journey. Patients prescribed olaparib appear to have had a long cancer journey, sometimes with prior cancer ("I had breast cancer in 1996") and sometimes with a long interval from an ovarian cancer diagnosis; (2) Adherence. Despite this journey, patients were adherent to olaparib ("I set it for an alarm 15 min before I have to take [olaparib] and then exactly when I'm supposed to take it"); (3) Adherence Despite Challenges. Adherence continued despite side effects (although olaparib was "pretty tolerable"). This adherence also continued despite cost ("…for a month's supply, mine was $15,837… and my insurance covered some of it but not near enough"), and (4) Modifications in Perceptions of BRCA Status. Olaparib as cancer therapy influenced perceptions of BRCA mutations ("But I… I have to tell you, I'm grateful that I qualified to be on Lynparza®").
CONCLUSION
Although oral maintenance therapy for ovarian cancer is relatively new, patients appear willing to take olaparib long term; and they seem to take great lengths to remain adherent, despite having sometimes had a long cancer journey.
Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Ovarian Neoplasms; Phthalazines; Piperazines; Quality of Life
PubMed: 35146567
DOI: 10.1007/s00520-022-06879-w -
Archives of Gynecology and Obstetrics Aug 2013Ovarian cancer (OC) is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at advanced stage with poor prognosis. Currently,... (Review)
Review
BACKGROUND
Ovarian cancer (OC) is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at advanced stage with poor prognosis. Currently, surgical tumor debulking followed by chemotherapy based on platinum and taxane is the standard treatment for advanced OC. However, these patients remain at great risk for recurrence and developing drug resistance. Therefore, new treatment strategies are needed to improve outcomes for patients with advanced and recurrent OC. Olaparib (AZD2281, KU-0059436), as one of the best understood Poly-(ADP-ribose) polymerase (PARP) inhibitor targeting DNA repair mechanisms, caused more and more attention. Clinical trial data of Olaparib had been cumulated, which applied as the single-agent in relapsed OC monotherapy, especially for BRCA mutation associated OC.
METHODS
In this review, we demonstrated the mechanism of PARP inhibitors and summarized clinical trial data and clinical development of Olaparib targeted OC in order to address a new promising therapy strategy for advanced relapsed OC.
CONCLUSION
Given the unprecedented clinical potential of Olaparib, the further research on Olaparib will have great significance in selection of OC patient populations that will respond to treatment.
Topics: Antineoplastic Agents; Female; Genes, BRCA1; Genes, BRCA2; Humans; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 23619942
DOI: 10.1007/s00404-013-2856-2 -
Drugs of Today (Barcelona, Spain : 1998) Jan 2016Olaparib, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, is the first FDA-approved drug in its class for patients with ovarian cancer, specifically in a subset of... (Review)
Review
Olaparib, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, is the first FDA-approved drug in its class for patients with ovarian cancer, specifically in a subset of patients with BRCA mutations and prior chemotherapy treatments. PARP inhibitors have had other implications in different solid tumor types including breast, gastric and pancreatic malignancies. In light of the recent FDA approval of olaparib for the treatment of ovarian cancer, this article aims to outline the mechanisms and implications of the drug. With a favorable adverse event profile and improved outcomes, including progression-free survival, olaparib has demonstrated augmentation to therapeutic options in the treatment of ovarian cancer.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Female; Humans; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 26937492
DOI: 10.1358/dot.2016.52.1.2440714 -
Expert Opinion on Investigational Drugs Oct 2012Ovarian cancer is the most important cause of gynecological cancer-related mortality. Conventional treatments for advanced or recurrent disease offer limited results in... (Review)
Review
INTRODUCTION
Ovarian cancer is the most important cause of gynecological cancer-related mortality. Conventional treatments for advanced or recurrent disease offer limited results in terms of long-term responses and survival. Researches have recently focused on target therapies, which represent a new, promising, therapeutic approach, able to maximizing tumor kill and minimizing toxicity. The family of polyadenosine diphosphate-ribose polymerase (PARP) inhibitors is currently one of the most hopeful and investigated alternatives.
AREAS COVERED
Preclinical and clinical studies of Olaparib , the most investigated PARP inhibitor in ovarian cancer, are analyzed and discussed. Data were obtained by searching for all English peer-reviewed articles on Medline, on Cochrane Database and all on-going Phase I and II studies registered on National Cancer Institute Clinical Trials; also any related abstracts recently presented on Olaparib at major international congresses will be included.
EXPERT OPINION
Bad prognosis and drug resistance usually affect ovarian cancer. Recent trends toward the knowledge of molecular-specific pathways have produced new target drugs. PARP inhibition mediated by Olaparib in BRCA1 (breast cancer 1) and BRCA2 (breast cancer 2)-mutated and in sporadic ovarian cancer represents a promising field of investigation. Further studies are needed to confirm initial exciting results.
Topics: Antineoplastic Agents; Female; Humans; Ovarian Neoplasms; Phthalazines; Piperazines; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 22788971
DOI: 10.1517/13543784.2012.707189 -
European Journal of Cancer (Oxford,... Nov 2023Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose.
METHODS
This cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC) within no-effect boundaries. These boundaries were set at 0.57-1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets.
RESULTS
Of 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC was 1.45 (90% CI 1.27-1.65). No grade ≥3 adverse events were reported during the study.
CONCLUSIONS
Boosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.
Topics: Humans; Cross-Over Studies; Cytochrome P-450 CYP3A; Piperazines; Cobicistat
PubMed: 37806255
DOI: 10.1016/j.ejca.2023.113346 -
NEJM Evidence Sep 2022BACKGROUND: Preclinical studies and results of a phase 2 trial of abiraterone and olaparib suggest a combined antitumor effect when the poly(adenosine...
BACKGROUND: Preclinical studies and results of a phase 2 trial of abiraterone and olaparib suggest a combined antitumor effect when the poly(adenosine diphosphate[ADP]-ribose) polymerase inhibitor olaparib is combined with next-generation hormonal agent abiraterone to treat metastatic castration-resistant prostate cancer (mCRPC). METHODS: We conducted a double-blind, phase 3 trial of abiraterone and olaparib versus abiraterone and placebo in patients with mCRPC in the first-line setting. Patients were enrolled regardless of homologous recombination repair gene mutation (HRRm) status. HRRm status was determined following enrollment by tumor tissue and circulating tumor DNA tests. Patients were randomly assigned (1:1) to receive abiraterone (1000 mg once daily) plus prednisone or prednisolone with either olaparib (300 mg twice daily) or placebo. The primary end point was imaging-based progression-free survival (ibPFS) by investigator assessment. Overall survival was among the secondary end points. RESULTS: At this planned primary analysis at the first data cutoff, median ibPFS was significantly longer in the abiraterone and olaparib arm than in the abiraterone and placebo arm (24.8 vs. 16.6 months; hazard ratio, 0.66; 95% confidence interval [CI], 0.54 to 0.81; P<0.001) and was consistent with blinded independent central review (hazard ratio, 0.61; 95% CI, 0.49 to 0.74). At this data cutoff, overall survival data were immature (28.6% maturity; hazard ratio, 0.86; 95% CI, 0.66 to 1.12; P=0.29). The safety profile of olaparib and abiraterone was consistent with the known safety profiles of the individual drugs. The most common adverse events in the abiraterone and olaparib arm were anemia, fatigue/asthenia, and nausea. CONCLUSIONS: At primary analysis at this first data cutoff, abiraterone combined with olaparib significantly prolonged ibPFS compared with abiraterone and placebo as first-line treatment for patients with mCRPC enrolled irrespective of HRRm status. (Funded by AstraZeneca and Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; ClinicalTrials.gov number, NCT03732820.)
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Antineoplastic Combined Chemotherapy Protocols; Androstenes; Phthalazines; Piperazines
PubMed: 38319800
DOI: 10.1056/EVIDoa2200043