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Expert Opinion on Pharmacotherapy 2016Despite recent advances in the management of epithelial ovarian cancer, overall survival rates remain poor, and there is a pressing need to develop novel therapeutic... (Review)
Review
INTRODUCTION
Despite recent advances in the management of epithelial ovarian cancer, overall survival rates remain poor, and there is a pressing need to develop novel therapeutic agents and maintenance strategies to improve outcomes for women with this disease. Olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, has demonstrated antitumor activity in women with ovarian cancer, associated with homologous recombination deficiency.
AREAS COVERED
This review outlines the rationale for PARP inhibitor therapy in ovarian cancer and summarizes the efficacy and tolerability data for olaparib to date. Ongoing phase III clinical trials of olaparib in ovarian cancer will be discussed.
EXPERT OPINION
There are a number of issues regarding the optimal use of olaparib in ovarian cancer, including the identification of a homologous recombination deficiency signature to predict treatment response, establishment of the optimal treatment setting (maintenance or relapsed disease), and evaluation of cost-effectiveness. Finally, the long term consequences of PARP inhibitors, including the risk of myelodysplasia and acute myeloid leukemia need to be quantified in ongoing large phase III clinical trials.
Topics: Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Female; Humans; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic
PubMed: 26967466
DOI: 10.1517/14656566.2016.1165205 -
American Journal of Health-system... Jul 2016The pharmacology, clinical efficacy, safety, dosage and administration, and role in therapy of olaparib, a first-in-class treatment for advanced treatment-refractory... (Review)
Review
PURPOSE
The pharmacology, clinical efficacy, safety, dosage and administration, and role in therapy of olaparib, a first-in-class treatment for advanced treatment-refractory ovarian cancer, are reviewed.
SUMMARY
Olaparib (Lynparza, AstraZeneca) is an oral inhibitor of poly(ADP-ribose) polymerase (PARP) proteins that play a key role in DNA repair and genomic stability. Olaparib is indicated for use in treating certain patients with advanced, recurrent ovarian cancer who have mutations of the breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2). In patients with BRCA-mutated cancers, olaparib blocks vital PARP-mediated tumor cell DNA repair mechanisms, leading to "synthetic lethality" and selective tumor cell death. In Phase II clinical trials including patients with platinum-sensitive, platinum-resistant, and platinum-refractory ovarian cancers, olaparib significantly improved progression-free survival, with similar rates of response reported in patients with BRCA1- and BRCA2-mutated disease. Olaparib is generally well tolerated; the most commonly reported adverse events in clinical trials were mild nausea, fatigue, vomiting, and diarrhea. Severe anemia and severe fatigue can occur in association with olaparib treatment. Concurrent administration of olaparib and strong or moderate inducers or inhibitors of cytochrome P-450 isozyme 3A should be avoided, as use of those agents may alter plasma concentrations of olaparib.
CONCLUSION
Olaparib is a novel PARP inhibitor that is efficacious and well tolerated in patients with BRCA-mutated advanced ovarian cancers who have received three or more lines of prior treatment.
Topics: Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Female; Humans; Mutation; Ovarian Neoplasms; Phthalazines; Piperazines; Treatment Outcome
PubMed: 27385701
DOI: 10.2146/ajhp150550 -
Journal of Oncology Pharmacy Practice :... Oct 2022This review will provide an overview of the use rucaparib and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC) with the goal to assist... (Review)
Review
OBJECTIVE
This review will provide an overview of the use rucaparib and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC) with the goal to assist the clinician's decision-making process when considering these agents for an individual patient.
DATA SOURCES
Searches were conducted in PubMed, relevant meeting abstracts, clinicaltrials.gov, and United States Food and Drug Administration (FDA) documents to identify literature published through July 1, 2021, related to use of rucaparib and olaparib for treatment of prostate cancer.
DATA SUMMARY
In May 2020, the FDA approved rucaparib and olaparib for treatment of mCRPC that is homologous recombination repair (HRR)-deficient. Both agents are approved for previously-treated patients, but there are notable differences in strength of evidence, outcomes studied, required HRR alteration, and required prior therapies. In patients who qualify for therapy, additional factors that may help guide choice of PARP inhibitor include baseline organ function, drug interaction potential, toxicity profiles, and financial factors.
CONCLUSIONS
Rucaparib and olaparib have the potential to improve outcomes for patients with HRR-deficient mCRPC. Differences in strength of evidence and patient- and drug-specific characteristics will assist the clinician when choosing between agents.
Topics: Humans; Indoles; Male; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant
PubMed: 35440240
DOI: 10.1177/10781552221094308 -
Prescrire International Jan 2017Standard post-surgical (adjuvant) chemotherapy for ovarian cancer is based on a platinum salt, and may be repeated if relapse occurs more than six months after the end... (Review)
Review
Standard post-surgical (adjuvant) chemotherapy for ovarian cancer is based on a platinum salt, and may be repeated if relapse occurs more than six months after the end of chemo- therapy. Olaparib inhibits enzymes involved in DNA repair. It is claimed to have an antitumour effect, especially in the presence of deleterious BRCA muta- tions. Olaparib has been authorised in the EU for continuous single-agent therapy after the end of platinum-based chemotherapy in patients with "plati- num-sensitive" BRCA-positive ovarian cancer who have already received at least two lines of platinum-based che- motherapy and entered complete or partial remission after the last course of treatment. Clinical evaluation of olaparib is based on a randomised, double-blind, placebo-controlled trial in 265 patients who were recruited regardless of their BRCA status. After a median follow-up of 37 months, patients treated with olaparib showed no survival advan- tage, whether or not their tumour harboured BRCA mutations. The time to radiological progression was pro- longed by several months. An inher- ently unreliable post hoc analysis suggested that olaparib delayed the need for further chemotherapy. Olaparib exposes these patients in remission to frequent adverse effects, including nausea, vomiting, and impaired haematopoiesis. Olaparib can also cause life-threatening myelo- dysplastic syndrome, acute myeloid leukaemia, and haemorrhage. Olaparib is metabolised in the liver, mainly by cytochrome P450 isoenzymes CYP3A4 and CYP3A5. It is also a P-glycoprotein substrate and is likely to inhibit CYP3A4, P-glycopro- tein and other carrier proteins. Multiple pharmacokinetic interactions are also likely. Treatment with olaparib requires patients to take eight capsules twice a day, between meals. In practice, in early 2016, expectations of patients with ovarian cancer who have received at least two lines of chemotherapy are high, as they have short life expectancy and no sat- isfactory treatment options. Yet treat- ment with olaparib after the end of platinum-based chemotherapy still has an unfavourable harm-benefit bal- ance: patients derive no proven ben- efit, but adverse effects are frequent and sometimes fatal.
Topics: Anemia; Drug Interactions; Female; Genes, BRCA1; Genes, BRCA2; Hemorrhage; Humans; Leukemia, Myeloid, Acute; Maintenance Chemotherapy; Myelodysplastic Syndromes; Nausea; Ovarian Neoplasms; Phthalazines; Piperazines; Pneumonia; Poly(ADP-ribose) Polymerase Inhibitors; Risk Assessment; Survival Rate; Treatment Outcome; Vomiting
PubMed: 30730634
DOI: No ID Found -
Gan To Kagaku Ryoho. Cancer &... Apr 2023Olaparib, a PARP inhibitor, was approved in 2018 for BRCA1/2 gene mutation and HER2-negative inoperable or recurrent breast cancer with previous chemotherapy. Olaparib...
Olaparib, a PARP inhibitor, was approved in 2018 for BRCA1/2 gene mutation and HER2-negative inoperable or recurrent breast cancer with previous chemotherapy. Olaparib is an important drug with minor adverse events compared to chemotherapeutic drugs. In addition, it is expected to exert a high therapeutic effect on breast cancer with BRCA mutations due to its characteristics. We report a case of BRCA2-mutated breast cancer in a patient in whom olaparib was initiated. The patient complained of strong nausea; however, the treatment could be continued by reducing the dose of olaparib to 400 mg and using multiple drugs such as antiemetics and anxiolytics in advance.
Topics: Humans; Female; BRCA1 Protein; Neoplasm Recurrence, Local; Antineoplastic Agents; Breast Neoplasms; Ovarian Neoplasms; Mutation
PubMed: 37066460
DOI: No ID Found -
Cancer Letters Feb 2024Although Poly (ADP-ribose) polymerase (PARP) inhibitors have been clinically approved for cancers with BRCA mutations and are known to augment radiotherapy responses,...
Although Poly (ADP-ribose) polymerase (PARP) inhibitors have been clinically approved for cancers with BRCA mutations and are known to augment radiotherapy responses, their roles in promoting the abscopal effect and mediating immunotherapy in BRCA-proficient hepatocellular carcinoma (HCC) remain underexplored. Our study elucidates that olaparib enhances the radio-sensitivity of HCC cells. Coadministration of olaparib and irradiation induces significant DNA damage by generating double-strand breaks (DSBs), as revealed both in vitro and in immune-deficient mice. These DSBs activate the cGAS-STING pathway, initiating immunogenic cell death in abscopal tumors. STING activation reprograms the immune microenvironment in the abscopal tumors, triggering the release of type I interferon and chemokines, including CXCL9, CXCL10, CXCL11, and CCL5. This in turn amplifies T cell priming against tumor neoantigens, leading to an influx of activated, neoantigen-specific CD8 T-cells within the abscopal tumors. Furthermore, olaparib attenuated the immune exhaustion induced by radiation and enhances the responsiveness of HCC to immune checkpoint inhibitors. Collectively, our data advocate that a synergistic regimen of PARP inhibitors and radiotherapy can strategically reinforce both local (primary) and systemic (abscopal) tumor control, bolstering HCC susceptibility to immunotherapy.
Topics: Animals; Mice; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Liver Neoplasms; Phthalazines; Cell Line, Tumor; Tumor Microenvironment; Piperazines
PubMed: 38048841
DOI: 10.1016/j.canlet.2023.216507 -
Expert Opinion on Pharmacotherapy Oct 2021: Men with prostate cancer undergoing castration will eventually progress. In addition to androgen receptor pathway inhibitors (like abiraterone and enzalutamide) or... (Review)
Review
: Men with prostate cancer undergoing castration will eventually progress. In addition to androgen receptor pathway inhibitors (like abiraterone and enzalutamide) or chemotherapy (like docetaxel), exists olaparib, a relatively new drug that interferes with the base excision repair (BER) pathway mainly due to selective inhibition of Poly ADP-ribose polymerase (PARP) 1 and 2.: Herein, the authors evaluate the basic characteristics of olaparib, including its pharmacokinetics, mechanism of action, efficacy, and safety profile. The authors also provide their expert opinion and future perspectives for the place of this drug in the current treatment armamentarium.: Olaparib is the first drug to prove that genetic sequencing and precise medicine is a viable and important option for prostate cancer patients. In patients with deletions in preselected genes, its efficacy renders it as a viable option for second- or third-line management of metastatic castrate resistance prostate cancer (mCRPC). This fact, along with its acceptable toxicity profile, provide physicians with a new weapon in their armamentarium against this extremely difficult to treat disease.
Topics: Humans; Male; Phenylthiohydantoin; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant; Treatment Outcome
PubMed: 34252319
DOI: 10.1080/14656566.2021.1952983 -
International Journal of Cancer Aug 2023In the primary analysis of the phase III OlympiAD trial, olaparib significantly prolonged progression-free survival (PFS) vs chemotherapy treatment of physician's choice... (Randomized Controlled Trial)
Randomized Controlled Trial
In the primary analysis of the phase III OlympiAD trial, olaparib significantly prolonged progression-free survival (PFS) vs chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (mBC). We report subgroup analyses for the final analysis at a median OS follow-up of 18.9 months (olaparib) and 15.5 months (TPC). Patients (N = 302) with gBRCAm, HER2-negative mBC and ≤2 previous lines of chemotherapy for mBC were randomized 2:1 to open-label olaparib (300 mg twice daily) or TPC. All subgroup analyses were prespecified except site of metastases. Investigator-assessed median PFS was 8.0 months (95% confidence interval [CI] 5.8-8.4; 176/205 events) for olaparib and 3.8 months (95% CI 2.8-4.2; 83/97 events) for TPC (hazard ratio 0.51, 95% CI 0.39-0.66). In subgroup analyses, median PFS hazard ratios (95% CI) favored olaparib: hormone receptor status (triple-negative: 0.47, 0.32-0.69; hormone receptor-positive: 0.52, 0.36-0.75); gBRCAm (BRCA1: 0.49, 0.35-0.71; BRCA2: 0.49, 0.33-0.74); site of metastases (visceral/CNS: 0.53, 0.40-0.71; non-visceral: 0.45, 0.23-0.98); prior chemotherapy for mBC (yes: 0.51, 0.38-0.70; no: 0.49, 0.30-0.82); prior platinum-based chemotherapy for BC (yes: 0.49, 0.30-0.83; no: 0.50, 0.37-0.69); progressive disease at randomization (yes: 0.48, 0.35-0.65; no: 0.61, 0.36-1.07). Investigator-assessed objective response rates were higher across all subgroups with olaparib (35-68%) vs TPC (5-40%). Global health status/health-related quality of life increased in all subgroups with olaparib vs decreased/no change with TPC. These data confirm the consistency of olaparib benefit across patient subgroups in OlympiAD.
Topics: Female; Humans; BRCA1 Protein; Breast Neoplasms; Germ-Line Mutation; Ovarian Neoplasms; Phthalazines; Quality of Life
PubMed: 36971103
DOI: 10.1002/ijc.34525 -
European Journal of Cancer (Oxford,... Jul 2022Based on PROfound, olaparib is approved for patients with metastatic castration-resistant prostate cancer following disease progression on at least enzalutamide or... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Based on PROfound, olaparib is approved for patients with metastatic castration-resistant prostate cancer following disease progression on at least enzalutamide or abiraterone and who carry relevant alterations in DNA repair genes. To facilitate continued olaparib treatment as long as the patient derives benefit, we describe further safety assessments from PROfound focusing on the four most common adverse events (AEs) and events of special interest.
METHODS
Patients were randomized (2:1) to olaparib tablets (300 mg bid) or control (enzalutamide or abiraterone) until disease progression or unacceptable toxicity. Safety was assessed through AE reporting and laboratory assessments. Safety data were also collected from all patients in the control group who experienced radiographic disease progression and subsequently crossed over to olaparib treatment.
RESULTS
256 patients received olaparib and 130 control. Incidence rates for the four most commonly occurring AEs in the olaparib group (all-causality) were anaemia 50%, nausea 43%, fatigue/asthenia 42% and decreased appetite 31%. All were mostly Grade 1 and 2 and all peaked within the first 2 months of treatment as the events were managed where appropriate, primarily with dose interruptions or dose reductions. The extent of bone metastases at baseline or prior taxane use was not associated with the rate of anaemia. Pneumonitis was reported in 2% and 1.5% of patients in the olaparib and control groups, respectively, and one patient (0.4%) in the olaparib group experienced an event of MDS/AML after a 30-day follow-up period. Venous thromboembolic events occurred in 8% of olaparib and 3% of control patients.
CONCLUSIONS
The four most common AEs observed in PROfound were generally manageable without the need for treatment discontinuation, allowing patients to remain on treatment for as long as they were deriving clinical benefit.
CLINICALTRIALS
gov registration number: NCT02987543.
Topics: Anemia; Disease Progression; Humans; Male; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant
PubMed: 35598359
DOI: 10.1016/j.ejca.2022.04.016 -
The New England Journal of Medicine Mar 2021
Topics: Humans; Male; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant
PubMed: 33761222
DOI: 10.1056/NEJMc2100225