Olaparib in the treatment of ovarian cancer

2019 ◽  
Vol 15 (30) ◽  
pp. 3435-3449 ◽  
Author(s):  
Christina R Washington ◽  
Debra L Richardson ◽  
Kathleen N Moore
Keyword(s):  
Ovarian Cancer ◽  
Disease Free Survival ◽  
Front Line ◽  
Platinum Sensitive ◽  
Formidable Challenge ◽  
Platinum Based Chemotherapy ◽  
Measurable Disease ◽  
Treatment Naïve ◽  
Line Setting ◽  
Disease Free

The poly ADP ribose polymerase olaparib is currently approved in front line BRCA-associated epithelial ovarian cancer (EOC), platinum-sensitive recurrence agnostic to BRCA status and for gBRCA as treatment in the fourth line and beyond. Women who are diagnosed with advanced stage EOC face a formidable challenge in overcoming their disease and achieving long-term, disease-free survival. The qualifier here is disease free. EOC is largely exquisitely chemosensitive, especially in the treatment naive (first line) setting and the expectation is that the vast majority of women will complete front line platinum-based chemotherapy with a response. When unselected (not selected by BRCA) women are enrolled on clinical trials, the response rate among those who have measurable disease at the time of chemotherapy initiation is 48% for carboplatin/paclitaxel and 67% for carboplatin/paclitaxel plus bevacizumab. When one considers the addition of women who start chemotherapy without measurable disease, they will likely also end chemotherapy without measurable disease and the overall rate of no evidence of disease at conclusion of chemotherapy approaches 80%. Despite this, the majority of women will suffer relapse of their disease, typically within the first 3 years following completion of therapy. Once recurrent, the disease is highly treatable for many years but no longer considered curable. This review will cover indications for olaparib in ovarian cancer as well as ongoing combination trials and rationale for these combinations.

scholarly journals How to sequence treatment in relapsed ovarian cancer

2020 ◽  
Author(s):  
Sandro Pignata ◽  
Sabrina Chiara Cecere
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Disease ◽  
Recurrent Ovarian Cancer ◽  
Platinum Resistance ◽  
Front Line ◽  
Related Factors ◽  
Drug Classes ◽  
Stage Disease ◽  
Platinum Based Chemotherapy ◽  
Line Setting

Numerous disease- and patient-related factors must be considered when selecting systemic therapy for recurrent ovarian cancer. Anti-angiogenics (bevacizumab) and poly(ADP-ribose) polymerase inhibitors (olaparib, niraparib, rucaparib) have an important role as maintenance of platinum-based chemotherapy for recurrent disease and their use in the first-line setting of advanced-stage disease is becoming established. As previous exposure to none, one or both of these drug classes is integral to selecting next therapy, front-line use impacts on options available to treat recurrent disease. A key strategy to delay platinum resistance and improve prognosis of recurrent disease is to alternate treatments with different mechanisms of action. The multiple mechanisms of trabectedin and its complementarity with platinum allow intercalation between platinum regimens in potentially platinum-responsive patients with recurrent disease.

scholarly journals Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial

2020 ◽  
Vol 38 (11) ◽  
pp. 1164-1174 ◽  
Author(s):  
Richard T. Penson ◽  
Ricardo Villalobos Valencia ◽  
David Cibula ◽  
Nicoletta Colombo ◽  
Charles A. Leath ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Liposomal Doxorubicin ◽  
Single Agent ◽  
Pegylated Liposomal Doxorubicin ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
End Point ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
Measurable Disease

PURPOSE A phase II study (ClinicalTrials.gov identifier: NCT00628251 ) showed activity of olaparib capsules versus pegylated liposomal doxorubicin in patients with germline BRCA-mutated platinum-resistant or partially platinum-sensitive relapsed ovarian cancer. We conducted a phase III trial (SOLO3) of olaparib tablets versus nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy. PATIENTS AND METHODS In this randomized, open-label trial, patients were randomly assigned 2:1 to olaparib 300 mg twice a day or physician’s choice single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan). The primary end point was objective response rate (ORR) in the measurable disease analysis set assessed by blinded independent central review (BICR). The key secondary end point was progression-free survival (PFS) assessed by BICR in the intent-to-treat population. RESULTS Of 266 randomly assigned patients, 178 were assigned to olaparib and 88 to chemotherapy. In patients with measurable disease (olaparib, n = 151; chemotherapy, n = 72), the BICR-assessed ORR was significantly higher with olaparib than with chemotherapy (72.2% v 51.4%; odds ratio [OR], 2.53 [95% CI, 1.40 to 4.58]; P = .002). In the subgroup who had received 2 prior lines of treatment, the ORR was 84.6% with olaparib and 61.5% with chemotherapy (OR, 3.44 [95% CI, 1.42 to 8.54]). BICR-assessed PFS also significantly favored olaparib versus chemotherapy (hazard ratio, 0.62 [95% CI, 0.43 to 0.91]; P = .013; median, 13.4 v 9.2 months). Adverse events were consistent with the established safety profiles of olaparib and chemotherapy. CONCLUSION Olaparib resulted in statistically significant and clinically relevant improvements in ORR and PFS compared with nonplatinum chemotherapy in patients with germline BRCA-mutated platinum-sensitive relapsed ovarian cancer who had received at least 2 prior lines of platinum-based chemotherapy.

Retrospective Analysis of Carboplatin and Paclitaxel as Initial Second-Line Therapy for Recurrent Epithelial Ovarian Carcinoma: Application Toward a Dynamic Disease State Model of Ovarian Cancer

2002 ◽  
Vol 20 (5) ◽  
pp. 1238-1247 ◽  
Author(s):  
Don S. Dizon ◽  
Martee L. Hensley ◽  
Elizabeth A. Poynor ◽  
Paul Sabbatini ◽  
Carol Aghajanian ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Recurrent Disease ◽  
Second Line ◽  
Front Line ◽  
New Paradigm ◽  
Second Line Therapy ◽  
Platinum Sensitive ◽  
Line Therapy ◽  
Platinum Based Chemotherapy ◽  
Line Chemotherapy

PURPOSE: The majority of patients with epithelial ovarian cancer (EOC) who achieve a complete remission with front-line chemotherapy develop recurrent disease. Carboplatin and paclitaxel are used for patients with platinum-sensitive recurrent disease, although there is little information regarding the response and survival in unselected patients treated with this strategy. We sought to determine the outcomes for patients with EOC treated with carboplatin and paclitaxel at the time of first recurrence. In addition, we sought to define a new paradigm for disease transition in patients with EOC. PATIENTS AND METHODS: Eighty-nine patients were identified who had a complete response to front-line platinum-based chemotherapy for EOC, relapsed 6 months after completion of front-line chemotherapy, and were treated with carboplatin and paclitaxel as second-line therapy. RESULTS: Eighty-four cases were available for analysis of survival end points, and 66 were assessable for response. The median follow-up was 27 months. The overall response rate was 70%. The median progression-free interval for the cohort was 13 months (95% confidence interval [CI], 10.7 to 13.8 months). The 3-year survival rate was 72% (95% CI, 59.4 to 86.1%). Toxicity was limited, and no deaths from treatment were observed. Using this data, it is possible to construct a disease states model of EOC, which provides risk estimates for transitions between clinically distinct categories. CONCLUSION: Re-treatment with carboplatin and paclitaxel is effective as initial therapy in recurrent EOC. This should form the basis of a randomized trial to determine the best agents for initial treatment of relapse from EOC in potentially platinum-sensitive patients.

Prolonged Disease-Free Survival by Maintenance Chemotherapy among Patients with Recurrent Platinum-Sensitive Ovarian Cancer

1998 ◽  
Vol 71 (2) ◽  
pp. 190-195 ◽  
Author(s):  
Gamal H. Eltabbakh ◽  
M.Steven Piver ◽  
Ronald E. Hempling ◽  
Fernando O. Recio ◽  
Leslie E. Blumenson
Keyword(s):  
Ovarian Cancer ◽  
Disease Free Survival ◽  
Maintenance Chemotherapy ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Disease Free

scholarly journals Optimized Prediction of Extreme Treatment Outcomes in Ovarian Cancer

2015 ◽  
Vol 14s5 ◽  
pp. CIN.S30803 ◽  
Author(s):  
Burook Misganaw ◽  
Eren Ahsen ◽  
Nitin Singh ◽  
Keith A. Baggerly ◽  
Anna Unruh ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Disease Free Survival ◽  
Predictive Biomarkers ◽  
Training Data ◽  
Ovarian Carcinomas ◽  
P Values ◽  
Free Survival ◽  
Platinum Based Chemotherapy ◽  
Extreme Treatment ◽  
Disease Free

Ovarian cancer is the fifth leading cause of death among female cancers. Front-line therapy for ovarian cancer is platinum-based chemotherapy. However, the response of patients is highly nonuniform. The TCGA database of serous ovarian carcinomas shows that ~10% of patients respond poorly to platinum-based chemotherapy, with tumors relapsing in seven months or less. Another 10% or so enjoy disease-free survival of three years or more. The objective of the present research is to identify a small number of highly predictive biomarkers that can distinguish between the two extreme responders and then extrapolate to all patients. This is achieved using the lone star algorithm that is specifically developed for biological applications. Using this algorithm, we are able to identify biomarker panels of 25 genes (of 12,000 genes) that can be used to classify patients into one of the three groups: super responders, medium responders, and nonresponders. We are also able to determine a discriminant function that can divide the entire patient population into two classes, such that one group has a clear survival advantage over the other. These biomarkers are developed using the TCGA Agilent platform data and cross-validated on the TCGA Affymetrix platform data, as well as entirely independent data from Tothill et al. The P-values on the training data are extremely small, sometimes below machine zero, while the P-values on cross-validation are well below the widely accepted threshold of 0.05.

Phase II consolidation trial with anti-Lewis-Y monoclonal antibody (hu3S193) in platinum-sensitive ovarian cancer after a second remission

2021 ◽  
pp. ijgc-2020-002239
Author(s):  
Oren Smaletz ◽  
Gustavo Ismael ◽  
Maria Del Pilar Estevez-Diz ◽  
Ivana L O Nascimento ◽  
Ana Luiza Gomes de Morais ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Monoclonal Antibody ◽  
Epithelial Ovarian Cancer ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Complete Response ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
Lewis Y

ObjectiveTo investigate the efficacy and safety of hu3S193, a humanized anti-Lewis-Y monoclonal antibody, as a consolidation strategy in patients with platinum-sensitive recurrent epithelial ovarian cancer who achieved a second complete response after salvage platinum-doublet chemotherapy.MethodsThis single-arm phase II study accrued patients with recurrent epithelial ovarian cancer with Lewis-Y expression by immunohistochemistry who had achieved a second complete response after five to eight cycles of platinum-based chemotherapy. Patients received intravenous infusions of hu3S193, 30 mg/m2 every 2 weeks starting no more than 8 weeks after the last dose of chemotherapy and continuing for 12 doses, until disease progression, or unacceptable toxicity. The primary endpoint was progression-free survival of the second remission. Secondary objectives were safety and pharmacokinetics.ResultsTwenty-nine patients were enrolled. Most had a papillary/serous histology tumor (94%), stage III disease at diagnosis (75%), and five (17%) underwent secondary cytoreduction before salvage chemotherapy. Two patients were not eligible for efficacy but were considered for toxicity analysis. Eighteen patients (62%) completed the full consolidation treatment while nine patients progressed on treatment. At the time of analysis, 23 patients (85%) of the eligible population had progressed and seven of these patients (26%) had died. Median progression-free survival of the second remission was 12.1 months (95% CI: 10.6–13.9), with a 1-year progression-free survival of the second remission rate of 50.1%. The trial was terminated early since it was unlikely that the primary objective would be achieved. The most commonly reported treatment-related adverse events were nausea (55%) and vomiting (51%).ConclusionsHu3S193 did not show sufficient clinical activity as consolidation therapy in patients with recurrent epithelial ovarian cancer who achieved a second complete response after platinum-based chemotherapy.Trial registrationNCT01137071.

scholarly journals Development of a Genomic Signatures-Based Predictor of Initial Platinum-Resistance in Advanced High-Grade Serous Ovarian Cancer Patients

2021 ◽  
Vol 10 ◽  
Author(s):  
Yuan Li ◽  
Xiaolan Zhang ◽  
Yan Gao ◽  
Chunliang Shang ◽  
Bo Yu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Predictive Accuracy ◽  
Predictive Performance ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Single Nucleotide Variants ◽  
Tissue Samples ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy

BackgroundHigh grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet.MethodsNinety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients.ResultsA high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1–100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%.ConclusionsA multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.

scholarly journals Maintenance with Trabectedin in the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer

2019 ◽  
Vol 12 (2) ◽  
pp. 447-455 ◽  
Author(s):  
Eva María Guerra Alía ◽  
Cayetano Sempere Ortega ◽  
Alfonso Cortés Salgado ◽  
Concepción Sanchez Martínez ◽  
Julio Galindo Álvarez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Pegylated Liposomal Doxorubicin ◽  
Abdominal Distension ◽  
Recurrent Ovarian Cancer ◽  
Response To Treatment ◽  
Case Presentation ◽  
Good Tolerance ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
Selection Of

Ovarian cancer is the seventh most common type of cancer and the fifth leading cause of cancer death among women worldwide. The current usual therapeutic approach in this disease includes optimal cytoreductive therapy followed by platinum-based adjuvant chemotherapy, along with neoadjuvant chemotherapy prior to surgery in selected cases. The platinum-free interval (PFI) continues to be the most useful tool to assist in the selection of the subsequent therapy and to predict response to treatment. The combination of trabectedin and pegylated liposomal doxorubicin (PLD) is useful in patients with partially platinum-sensitive recurrent ovarian cancer, in patients who have previously received two or more platinum-based chemotherapy regimens, in patients who have already experienced a platinum-induced hypersensitivity reaction and in patients who have previously failed to respond to a platinum-based treatment. Case Presentation: A 64-years-old postmenopausal woman with pain, abdominal distension, and an altered intestinal transit and with partially platinum-sensitive recurrent ovarian cancer, was successfully treated with a second line of trabectedin chemotherapy in combination with PLD, followed by trabectedin in monotherapy. This case proves the effectiveness of the combination of trabectedin and PLD and demonstrates how the administration of trabectedin, even in monotherapy, allows to maintain an adequate clinical response with good tolerance to the treatment during more than two years of drug administration.

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