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Journal of Clinical Oncology : Official... Jul 2022Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the... (Randomized Controlled Trial)
Randomized Controlled Trial
Olaparib With or Without Cediranib Versus Platinum-Based Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer (NRG-GY004): A Randomized, Open-Label, Phase III Trial.
PURPOSE
Platinum-based chemotherapy is the standard of care for platinum-sensitive ovarian cancer, but complications from repeated platinum therapy occur. We assessed the activity of two all-oral nonplatinum alternatives, olaparib or olaparib/cediranib, versus platinum-based chemotherapy.
PATIENTS AND METHODS
NRG-GY004 is an open-label, randomized, phase III trial conducted in the United States and Canada. Eligible patients had high-grade serous or endometrioid platinum-sensitive ovarian cancer. Patients were randomly assigned 1:1:1 to platinum-based chemotherapy, olaparib, or olaparib/cediranib. The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included activity within germline -mutated or wild-type subgroups and patient-reported outcomes (PROs).
RESULTS
Between February 04, 2016, and November 13, 2017, 565 eligible patients were randomly assigned. Median PFS was 10.3 (95% CI, 8.7 to 11.2), 8.2 (95% CI, 6.6 to 8.7), and 10.4 (95% CI, 8.5 to 12.5) months with chemotherapy, olaparib, and olaparib/cediranib, respectively. Olaparib/cediranib did not improve PFS versus chemotherapy (hazard ratio [HR] 0.86; 95% CI, 0.66 to 1.10; = .077). In women with germline mutation, the PFS HR versus chemotherapy was 0.55 (95% CI, 0.32 to 0.94) for olaparib/cediranib and 0.63 (95% CI, 0.37 to 1.07) for olaparib. In women without a germline mutation, the PFS HR versus chemotherapy was 0.97 (95% CI, 0.73 to 1.30) for olaparib/cediranib and 1.41 (95% CI, 1.07 to 1.86) for olaparib. Hematologic adverse events occurred more commonly with chemotherapy; however, nonhematologic adverse events were higher with olaparib/cediranib. In 489 patients evaluable for PROs, patients receiving olaparib/cediranib scored on average 1.1 points worse on the NFOSI-DRS-P subscale (97.5% CI, -2.0 to -0.2, = .0063) versus chemotherapy; no difference between olaparib and chemotherapy was observed.
CONCLUSION
Combination olaparib/cediranib did not improve PFS compared with chemotherapy and resulted in reduced PROs. Notably, in patients with a germline mutation, both olaparib and olaparib/cediranib had significant clinical activity.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Female; Humans; Indoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Platinum; Quinazolines
PubMed: 35290101
DOI: 10.1200/JCO.21.02011 -
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 -
Experimental Biology and Medicine... Sep 2021Sepsis is characterized by persistent systemic inflammation, which can cause multi-organ dysfunction. The poly polymerase-1 inhibitor olaparib possesses...
Sepsis is characterized by persistent systemic inflammation, which can cause multi-organ dysfunction. The poly polymerase-1 inhibitor olaparib possesses anti-inflammatory properties. This study aimed to assess the effects of olaparib (pre- and post-treatments) on sepsis, and to investigate whether it could suppress CD14 expression via the ERK pathway in polymicrobial sepsis and peritoneal macrophages models. Sepsis was induced by cecal ligation and puncture in C57BL/6 male mice. Fifty mice were randomly divided into five groups: The sham group was treated with vehicle or olaparib, the cecal ligation and puncture group with vehicle or with olaparib (5 mg/kg i.p.) 1 h before or 2 h after surgery. Olaparib pretreatment significantly improved the survival of septic mice (<0.001). Pre- and post-treatment of mice with olaparib partly alleviated cecal ligation and puncture-induced organ injury by decreasing the amounts of the pro-inflammatory mediators TNF-α and IL-6 as well as bacterial burden in the serum, peritoneal lavage fluid, and organs (<0.05). The protective effect of olaparib was associated with CD14 suppression via inhibition of ERK activation. Olaparib facilitated negative regulation of ERK-mediated CD14 expression, which may contribute to multi-organ injury in sepsis.
Topics: Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Inflammation; Inflammation Mediators; Lipopolysaccharide Receptors; Lung; Male; Mice; Phthalazines; Piperazines; Sepsis
PubMed: 34053236
DOI: 10.1177/15353702211015620 -
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 -
Journal of Gynecologic Oncology Jan 2024The PAOLA-1 trial (NCT02477644) reported final survival benefit associated with olaparib plus bevacizumab maintenance treatment of patients with advanced ovarian cancer...
Olaparib plus bevacizumab as a first-line maintenance treatment for patients with advanced ovarian cancer by molecular status: an updated PAOLA-1 based cost-effectiveness analysis.
OBJECTIVE
The PAOLA-1 trial (NCT02477644) reported final survival benefit associated with olaparib plus bevacizumab maintenance treatment of patients with advanced ovarian cancer (AOC) based on molecular status. Our aimed to compare the cost-effectiveness of olaparib plus bevacizumab for overall patients, patients with a breast cancer susceptibility genes (BRCA) mutation, homologous recombination deficiency (HRD), or HRD without BRCA mutations AOC from the context of the American healthcare system.
METHODS
Analysis of health outcomes in life-years (LYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) in various molecular status-based AOC patient at a $150,000/QALY of willingness-to-pay was performed using a state-transitioned Markov model with a 20-year time horizon. Meanwhile, sensitivity analyses assessments were also used to gauge the model's stability.
RESULTS
The ICERs of olaparib plus bevacizumab versus bevacizumab alone were $487,428 ($374,758), $249,579 ($191,649), $258,859 ($198,739), and $270,736 ($206,640) per QALY (LY) in the overall patients, patients with BRCA mutations, patients with HRD, and patients with HRD without BRCA mutations AOC, respectively, which indicated that The ICERs was higher than $150,000/QALY in the US. Progression-free survival (PFS) value and olaparib cost emerged as the primary influencing factors of these findings in the sensitivity analysis.
CONCLUSION
At current cost levels, olaparib plus bevacizumab treatment is not a cost-effective treatment for patients with AOC regardless of their molecular status in the US. However, this maintenance treatment may be more favorable health advantages for patients with BRAC mutations AOC.
Topics: Humans; Female; Bevacizumab; Ovarian Neoplasms; Cost-Effectiveness Analysis; Cost-Benefit Analysis; Carcinoma, Ovarian Epithelial; Phthalazines; Piperazines
PubMed: 37477106
DOI: 10.3802/jgo.2024.35.e2 -
The New England Journal of Medicine Aug 2020
Topics: Humans; Male; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant
PubMed: 32846073
DOI: 10.1056/NEJMc2023199 -
The Oncologist Jun 2018Olaparib is a poly(ADP-ribose) polymerase enzyme inhibitor that is approved for use in patients with advanced ovarian cancer (OC) and genetic mutations who have... (Review)
Review
UNLABELLED
Olaparib is a poly(ADP-ribose) polymerase enzyme inhibitor that is approved for use in patients with advanced ovarian cancer (OC) and genetic mutations who have received three or more prior lines of chemotherapy for maintenance treatment of recurrent OC that is in response to platinum-based chemotherapy regardless of mutation status and for human epidermal growth receptor factor 2-negative metastatic breast cancer with deleterious or suspected deleterious germline mutations who have previously been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Because olaparib is poorly soluble and requires advanced drug delivery techniques to ensure bioavailability, the originally approved 400 mg dose is taken as eight 50 mg capsules twice daily. An alternative melt-extrusion tablet formulation was developed to improve the pharmacokinetic and pharmacodynamic profile of olaparib and reduce the pill burden for patients. The recommended tablet dose is 300 mg twice daily (two 150 mg tablets). Phase III studies with the tablet formulation are ongoing for multiple tumor types. Two studies conducted with the olaparib tablet formulation have reported results: one in platinum-sensitive, -mutated recurrent OC (SOLO-2) and one that included patients with germline -mutated metastatic breast cancer (OlympiAD). The tablet is the approved formulation based on the SOLO-2 trial results. Because the capsule and tablet formulations have different bioavailability, physicians must strictly adhere to the dosing instructions provided in the prescribing information. The tablet offers greater convenience for most patients, especially when using olaparib for maintenance therapy. This review discusses the differences between the two formulations, dose determination, and guidance for use of olaparib tablets by patients with OC. Prior to implementing any changes in therapy, health care providers should engage their patients in discussion to support an informed transition between the formulations.
IMPLICATIONS FOR PRACTICE
Olaparib has recently been approved for maintenance treatment of recurrent ovarian cancer (OC) that is in response to platinum-based chemotherapy. The originally approved capsule formulation was dosed as 400 mg twice daily (eight 50 mg capsules). The recommended olaparib tablet dose is 300 mg twice daily (two 150 mg tablets). The tablet is the new approved formulation based on the SOLO-2 trial results. Because the capsule and tablet formulations have different bioavailability, physicians must strictly adhere to the dosing instructions provided in the prescribing information. The tablet offers greater convenience for most patients, especially when using olaparib for maintenance therapy. This review discusses the differences between the two formulations, dose determination, and guidance for use of olaparib tablets by patients with OC.
Topics: Antineoplastic Agents; Female; Humans; Ovarian Neoplasms; Phthalazines; Piperazines; Tablets
PubMed: 29593098
DOI: 10.1634/theoncologist.2017-0485 -
BMC Pulmonary Medicine Aug 2023Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated effectiveness in treating ovarian, breast, and other cancers, particularly those with... (Review)
Review
BACKGROUND
Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated effectiveness in treating ovarian, breast, and other cancers, particularly those with specific molecular subtypes including, but not limited to, BRCA1/2 mutations. Consequently, its utilization is expected to increase in the future. For this reason, it is important to acknowledge the potential for adverse events associated with olaparib, including the relatively rare but significant risk of drug-induced interstitial lung disease (DIILD). Since DIILD can lead to fatal outcomes, its early detection is crucial. The dissemination of knowledge regarding DIILD can be facilitated through case reports; however, specific reports of DIILD caused by olaparib have only been published in Japanese. To the best of our knowledge, this is the first report in English of our experience with three cases of DIILD caused by olaparib.
CASE PRESENTATION
Cases 1, 2, and 3 involved Japanese women with ovarian cancer who had been receiving olaparib at a dose of 600 mg/day. Case 1, a 72-year-old woman who had been on olaparib for 4 months, and case 2, a 51-year-old woman who had been on olaparib for 8 months, reported fever and general malaise. Chest computed tomography (CT) revealed pale ground glass opacity (GGO) similar to hypersensitivity pneumonitis. The severity grade was 2 in both cases. Case 3, a 78-year-old woman who had been on olaparib for 3 weeks, presented with cough and reported dyspnea on exertion. Chest CT revealed non-specific interstitial pneumonia and organizing pneumonia-like shadows. The severity grade was 4. Olaparib was discontinued in all cases. Case 1 received 0.6 mg/kg of prednisolone due to mild hypoxia, while prednisolone was not administered in case 2 due to the absence of hypoxia. Case 3 received steroid pulse therapy due to severe hypoxia. Olaparib administration was not resumed in any patient.
CONCLUSION
DIILD caused by olaparib in Japan, including the present three cases, commonly presents with GGO, similar to hypersensitivity pneumonitis on chest CT. The prognosis for the majority of patients is favorable; however, there have been instances of severe cases. Early recognition of drug-induced lung injury and further accumulation of cases is important.
Topics: Aged; Female; Humans; Middle Aged; BRCA1 Protein; BRCA2 Protein; East Asian People; Lung Diseases, Interstitial; Ovarian Neoplasms; Antineoplastic Agents
PubMed: 37553592
DOI: 10.1186/s12890-023-02569-3 -
Anticancer Research Jan 2022Epstein-Barr virus (EBV)-associated gastric cancer has been identified as a cancer subtype with definitive clinical and molecular characteristics. Although olaparib, a...
BACKGROUND
Epstein-Barr virus (EBV)-associated gastric cancer has been identified as a cancer subtype with definitive clinical and molecular characteristics. Although olaparib, a poly ADP ribose polymerase (PARP) inhibitor, is considered a potential effective agent for gastric cancer, the effect and underlying mechanism of olaparib on gastric cancer depending on EBV infection is not fully understood.
MATERIALS AND METHODS
EBV-positive SNU719 and EBV-negative SNU638 gastric cancer cell lines were used to identify the effects of olaparib using the trypan blue exclusion method and annexin V staining assay. To observe the underlying cellular signaling mechanisms of olaparib-induced cell death, Epstein-Barr virus nuclear antigen 1 (EBNA1) and signaling related molecule expression were assessed using transfection, silencing of specific genes using small interfering RNA (siRNA), western blotting and signaling inhibition assay.
RESULTS
Olaparib decreased the cell viability of EBV-positive SNU719 gastric cancer cells through caspase-3-dependent apoptosis in a dose dependent manner, whereas EBV-negative SNU638 gastric cancer cells showed drug resistance to olaparib. EBNA1 was expressed in SUN719 gastric cancer cells; however, ataxia telangiectasia and Rad3 related (ATR) and phosphorylated ATR kinase were expressed in SNU638 gastric cancer cells. EBNA1 transfection decreased ATR phosphorylation through p38 mitogen-activated protein kinase (MAPK) phosphorylation in SUN638 gastric cancer cells, and silencing of ATR kinase increased the susceptibility of these cells to olaparib treatment. Moreover, VE-821, an ATR kinase specific inhibitor, also increased the sensitivity of SNU638 cells to olaparib. In contrast, SB203580, a p38 MAPK inhibitor, inhibited this increase in sensitivity to olaparib by EBNA1 transfection.
CONCLUSION
Olaparib treatment led to different cellular responses depending on EBV infection in gastric cancer cell lines. These results provide new insights into the mechanism of olaparib-induced apoptosis in gastric cancer cells and suggest that EBV infection should be considered when developing new potential therapeutic agents for gastric cancer.
Topics: Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Gene Expression Regulation, Neoplastic; Herpesvirus 4, Human; Humans; Phthalazines; Piperazines; Signal Transduction; Stomach Neoplasms; p38 Mitogen-Activated Protein Kinases
PubMed: 34969765
DOI: 10.21873/anticanres.15513 -
Current Oncology (Toronto, Ont.) Aug 2023With the recent Health Canada approval of olaparib for high-risk, HER2-negative early breast cancer, physicians are now facing the practical challenges of integrating... (Review)
Review
With the recent Health Canada approval of olaparib for high-risk, HER2-negative early breast cancer, physicians are now facing the practical challenges of integrating olaparib into current management of triple-negative breast cancer (TNBC) and HR-positive, HER2-negative (HR+/HER2-) early breast cancer. This review provides perspectives on some of the challenges related to identification of olaparib candidates, with a focus on the latest guidance for germline BRCA testing and considerations regarding high-risk disease definitions. Updated treatment pathways are explored for both disease states, including other adjuvant treatment options such as pembrolizumab, capecitabine, and abemaciclib. Gaps in the current literature regarding the sequential or combined use of these adjuvant therapies are noted and future, potentially informative, studies are briefly examined.
Topics: Humans; Canada; Phthalazines; Piperazines; Triple Negative Breast Neoplasms
PubMed: 37623037
DOI: 10.3390/curroncol30080556