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Expert Opinion on Pharmacotherapy Mar 2021Advanced pancreatic cancer remains a lethal, incurable malignancy. Chemotherapy is the mainstay of systemic therapy consideration in metastatic pancreas cancer.... (Review)
Review
INTRODUCTION
Advanced pancreatic cancer remains a lethal, incurable malignancy. Chemotherapy is the mainstay of systemic therapy consideration in metastatic pancreas cancer. Homologous recombinant DNA repair mutations are reported in about 7% of pancreas cancer cases and have rapidly emerged as actionable mutations.
AREAS COVERED
A review was conducted of publications of PARP inhibitors in pancreatic malignancies with a focus on clinical trials with olaparib. This included a review of the phase II and phase III clinical trials of olaparib in pancreatic cancer.
EXPERT OPINION
Olaparib was compared to placebo in a randomized double blind trial in cases with advanced pancreatic cancer and germline mutations, with a clinical response or stable disease after at least 16 weeks of platinum based chemotherapy. Olaparib significantly improved progression free survival, [HR = -.53, = 0.0035] but did not improve overall survival. No differences in quality of life were noted between the two arms. Adverse events from olaparib were noted in 40% of treated patients. Objective response rate was 20% in olaparib arm and 10% in placebo treated arm. A careful consideration of the risks and benefits of this personalized therapy is advisable, prior to clinical application in germline BRCA1/2 mutated advanced pancreatic cancer.
Topics: Antineoplastic Agents; BRCA1 Protein; Humans; Mutation; Pancreatic Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Quality of Life
PubMed: 33094666
DOI: 10.1080/14656566.2020.1837113 -
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 -
Aktuelle Urologie Apr 2022
Topics: Humans; Male; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant
PubMed: 35345006
DOI: 10.1055/a-1562-3862 -
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 -
Expert Opinion on Investigational Drugs Jun 2017Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found... (Review)
Review
Basal-like breast cancer is characterized by being triple negative and aggressive. Defects in DNA repair is a promising therapeutic target as BRCA alterations are found in 11 to 42% of these tumors, with a frequency varying according to family history and ethnicity. The oral PARP inhibitors exploit this deficiency through a synthetic lethality and are considered as promising anticancer therapies, especially in patients harboring BRCA1 or BRCA 2 mutations. Areas covered: Olaparib is one of the most widely investigated PARP inhibitors. Here, the preclinical data, completed clinical trials and ongoing investigations are discussed. Expert opinion: PARP inhibitors show promising results in breast cancer. However, several issues are raised including the identification of biomarkers to predict treatment response and strategies to counteract emerging resistance. Moreover, the results from ongoing phase III trials of olaparib in breast cancer are still awaited.
Topics: Animals; Antineoplastic Agents; BRCA1 Protein; BRCA2 Protein; Biomarkers, Tumor; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Humans; Mutation; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 28395540
DOI: 10.1080/13543784.2017.1318847 -
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 -
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 -
Journal of Controlled Release :... May 2023Diffuse midline glioma H3K27-altered (DMG) is an aggressive, inoperable, predominantly paediatric brain tumour. Treatment strategies are limited, resulting in a median...
BACKGROUND AND PURPOSE
Diffuse midline glioma H3K27-altered (DMG) is an aggressive, inoperable, predominantly paediatric brain tumour. Treatment strategies are limited, resulting in a median survival of only 11 months. Currently, radiotherapy (RT), often combined with temozolomide, is considered the standard of care but remains palliative, highlighting the urgency for new therapies. Radiosensitisation by olaparib, an inhibitor of PARP1 and subsequently PAR-synthesis, is a promising treatment option. We assessed whether PARP1 inhibition enhances radiosensitivity in vitro and in vivo following focused ultrasound mediated blood-brain barrier opening (FUS-BBBO).
METHODS
Effects of PARP1 inhibition were evaluated in vitro using viability, clonogenic, and neurosphere assays. In vivo olaparib extravasation and pharmacokinetic profiling following FUS-BBBO was measured by LC-MS/MS. Survival benefit of FUS-BBBO combined with olaparib and RT was assessed using a patient-derived xenograft (PDX) DMG mouse model.
RESULTS
Treatment with olaparib in combination with radiation delayed tumour cell proliferation in vitro through the reduction of PAR. Prolonged exposure of low olaparib concentration was more efficient in delaying cell growth than short exposure of high concentration. FUS-BBBO increased olaparib bioavailability in the pons by 5.36-fold without observable adverse effects. A Cmax of 54.09 μM in blood and 1.39 μM in the pontine region was achieved following administration of 100 mg/kg olaparib. Although RT combined with FUS-BBBO mediated olaparib extravasation delayed local tumour growth, survival benefits were not observed in an in vivo DMG PDX model.
CONCLUSIONS
Olaparib effectively radiosensitises DMG cells in vitro and reduces primary tumour growth in vivo when combined with RT. Further studies are needed to investigate the therapeutic benefit of olaparib in suitable preclinical PDX models.
Topics: Humans; Mice; Animals; Chromatography, Liquid; Cell Line, Tumor; Tandem Mass Spectrometry; Glioma
PubMed: 37019285
DOI: 10.1016/j.jconrel.2023.03.058 -
Targeted Oncology Nov 2021Olaparib (Lynparza) is a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor approved for first-line maintenance treatment in adults with advanced ovarian... (Review)
Review
Olaparib (Lynparza) is a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor approved for first-line maintenance treatment in adults with advanced ovarian cancer who are in complete or partial response to first-line, platinum-based chemotherapy. Originally approved as monotherapy, olaparib is also approved to be administered in combination with bevacizumab in patients whose cancer is associated with homologous recombination deficiency (HRD), defined by either a BRCA1/2 mutation and/or genomic instability. In phase III trials, olaparib monotherapy significantly improved progression-free survival (PFS) relative to placebo (SOLO-1), as did olaparib plus bevacizumab relative to placebo plus bevacizumab (PAOLA-1), in patients with advanced ovarian cancer who had responded to platinum-based chemotherapy. In PAOLA-1, improvements in PFS with olaparib plus bevacizumab were not seen in patients with HRD-negative tumours relative to placebo plus bevacizumab. Both olaparib monotherapy and olaparib in combination with bevacizumab had generally manageable tolerability profiles. Olaparib, alone or in combination with bevacizumab, is a useful option for the first-line maintenance treatment of adults with HRD-positive, advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line, platinum-based chemotherapy.
Topics: Adult; Bevacizumab; Carcinoma, Ovarian Epithelial; Female; Humans; Maintenance Chemotherapy; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines
PubMed: 34623572
DOI: 10.1007/s11523-021-00842-1 -
JAMA Network Open Apr 2024Testing for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Testing for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is ongoing.
OBJECTIVE
To investigate whether progression-free survival (PFS) and overall survival (OS) of patients with high-grade epithelial ovarian cancer treated with maintenance olaparib or placebo differed between patients with a tumor BRCA-like genomic profile and patients without a tumor BRCA-like profile.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study was a secondary analysis of the PAOLA-1 randomized clinical trial that compared olaparib plus bevacizumab with placebo plus bevacizumab as maintenance treatment in patients with advanced high-grade ovarian cancer after a good response to first-line platinum with taxane chemotherapy plus bevacizumab, irrespective of germline or tumor BRCA1/2 mutation status. All patients with available tumor DNA were included in the analysis. The current analysis tested for an interaction between BRCA-like status and olaparib treatment on survival outcomes. The original trial was conducted between July 2015 and September 2017; at the time of data extraction for analysis in March 2022, a median follow-up of 54.1 months (IQR, 28.5-62.2 months) and a total follow-up time of 21 711 months was available, with 336 PFS and 245 OS events.
EXPOSURES
Tumor homologous recombination deficiency was assessed using the BRCA-like copy number aberration profile classifier. Myriad MyChoice CDx was previously measured. The trial was randomized between the olaparib and bevacizumab and placebo plus bevacizumab groups.
MAIN OUTCOMES AND MEASURES
This secondary analysis assessed hazard ratios (HRs) of olaparib vs placebo among biomarker strata and tested for interaction between BRCA-like status and olaparib treatment on PFS and OS, using Cox proportional hazards regression.
RESULTS
A total of 469 patients (median age, 60 [range 26-80] years) were included in this study. The patient cohort consisted of women with International Federation of Gynaecology and Obstetrics stage III (76%) high-grade serous (95%) ovarian cancer who had no evaluable disease or complete remission at initial or interval debulking surgery (76%). Thirty-one percent of the tumor samples (n = 138) harbored a pathogenic BRCA mutation, and BRCA-like classification was performed for 442 patients. Patients with a BRCA-like tumor had a longer PFS after olaparib treatment than after placebo (36.4 vs 18.6 months; HR, 0.49; 95% CI, 0.37-0.65; P < .001). No association of olaparib with PFS was found in patients with a non-BRCA-like tumor (17.6 vs 16.6 months; HR, 1.02; 95% CI, 0.68-1.51; P = .93). The interaction was significant (P = .004), and HRs and P values (for interaction) were similar in the relevant subgroups, OS, and multivariable analyses.
CONCLUSIONS AND RELEVANCE
In this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.
Topics: Pregnancy; Humans; Female; Adult; Middle Aged; Aged; Aged, 80 and over; Carcinoma, Ovarian Epithelial; Bevacizumab; BRCA1 Protein; Cohort Studies; BRCA2 Protein; Ovarian Neoplasms; Carcinoma; Genomics; Biomarkers; Phthalazines; Piperazines
PubMed: 38592722
DOI: 10.1001/jamanetworkopen.2024.5552