Poly-(ADP-ribose) polymerase inhibitors: paradigm shift in the first-line treatment of newly diagnosed advanced ovarian cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 721-727
Author(s):  
Fady Gh Haddad ◽  
Elias Karam ◽  
Elissar Moujaess ◽  
Hampig Raphael Kourie
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Excision Repair ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
First Line ◽  
Free Survival ◽  
Base Excision ◽  
Breast Cancer Gene

Debulking surgery associated with chemotherapy represent the backbone of ovarian cancer therapy. Adding bevacizumab has improved survival. Recently, PARP inhibitors were added in the first line as maintenance treatment for the patients who achieve a complete or partial response. These drugs act by blocking the activity of the PARP enzyme responsible for base-excision repair, and have shown positive responses when used for tumors lacking homologous recombination. Olaparib, niraparib and veliparib were evaluated and showed an increase in the duration of progression-free survival: 22.1 months (hazard ratio [HR] = 0.59), 13.8 (HR = 0.62) and 23.5 (HR = 0.68) with olaparib, niraparib and veliparib, respectively. This review describes the benefit of PARP inhibitors as maintenance therapy and discusses the efficacy according to breast cancer gene and homologous recombination status.

Incorporation of Pazopanib in Maintenance Therapy of Ovarian Cancer

2014 ◽  
Vol 32 (30) ◽  
pp. 3374-3382 ◽  
Author(s):  
Andreas du Bois ◽  
Anne Floquet ◽  
Jae-Weon Kim ◽  
Joern Rau ◽  
Josep M. del Campo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Growth Factor Receptor ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
First Line ◽  
Free Survival ◽  
Line Chemotherapy

PurposePazopanib is an oral, multikinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -1/-2/-3, platelet-derived growth factor receptor (PDGFR) -α/-β, and c-Kit. Preclinical and clinical studies support VEGFR and PDGFR as targets for advanced ovarian cancer treatment. This study evaluated the role of pazopanib maintenance therapy in patients with ovarian cancer whose disease did not progress during first-line chemotherapy.Patients and MethodsNine hundred forty patients with histologically confirmed cancer of the ovary, fallopian tube, or peritoneum, International Federation Gynecology Obstetrics (FIGO) stages II-IV, no evidence of progression after primary therapy consisting of surgery and at least five cycles of platinum-taxane chemotherapy were randomized 1:1 to receive pazopanib 800 mg once per day or placebo for up to 24 months. The primary end point was progression-free survival by RECIST 1.0 assessed by the investigators.ResultsMaintenance pazopanib prolonged progression-free survival compared with placebo (hazard ratio [HR], 0.77; 95% CI, 0.64 to 0.91; P = .0021; median, 17.9 v 12.3 months, respectively). Interim survival analysis based on events in 35.6% of the population did not show any significant difference. Grade 3 or 4 adverse events of hypertension (30.8%), neutropenia (9.9%), liver-related toxicity (9.4%), diarrhea (8.2%), fatigue (2.7%), thrombocytopenia (2.5%), and palmar-plantar erythrodysesthesia (1.9%) were significantly higher in the pazopanib arm. Treatment discontinuation related to adverse events was higher among patients treated with pazopanib (33.3%) compared with placebo (5.6%).ConclusionPazopanib maintenance therapy provided a median improvement of 5.6 months (HR, 0.77) in progression-free survival in patients with advanced ovarian cancer who have not progressed after first-line chemotherapy. Overall survival data to this point did not suggest any benefit. Additional analysis should help to identify subgroups of patients in whom improved efficacy may balance toxicity (NCT00866697).

Phase III Trial of High-Dose Sequential Chemotherapy With Peripheral Blood Stem Cell Support Compared With Standard Dose Chemotherapy for First-Line Treatment of Advanced Ovarian Cancer: Intergroup Trial of the AGO-Ovar/AIO and EBMT

2007 ◽  
Vol 25 (27) ◽  
pp. 4187-4193 ◽  
Author(s):  
Volker Möbus ◽  
Hannes Wandt ◽  
Norbert Frickhofen ◽  
Carmelo Bengala ◽  
Kim Champion ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Peripheral Blood Stem Cell ◽  
Standard Dose ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
High Dose ◽  
First Line ◽  
Sequential Chemotherapy ◽  
Free Survival ◽  
First Line Treatment

PurposeAlthough ovarian cancer is one of the most chemotherapy-sensitive solid tumors, cure after radical surgery and chemotherapy is uncommon. A randomized trial comparing high-dose sequential chemotherapy with peripheral blood stem cell (PBSC) support with platinum-based combination chemotherapy was conducted to investigate whether dose-intensification improves outcome.Patients and MethodsOne hundred forty-nine patients with untreated ovarian cancer were randomly assigned after debulking surgery to receive standard combination chemotherapy or sequential high-dose (HD) treatment with two cycles of cyclophosphamide and paclitaxel followed by three cycles of HD carboplatin and paclitaxel with PBSC support. HD melphalan was added to the final cycle. The median age was 50 years (range, 20 to 65 years) and International Federation of Gynecology and Obstetrics stage was IIb/IIc in 4%, III in 78%, and IV in 17%.ResultsSeventy-six percent of patients received all five cycles in the HD arm and the main toxicities were neuro-/ototoxicity, gastrointestinal toxicity, and infection and one death from hemorrhagic shock. After a median follow-up of 38 months, the progression-free survival was 20.5 months in the standard arm and 29.6 months in the HD arm (hazard ratio [HR], 0.84; 95% CI, 0.56 to 1.26; P, .40). Median overall survival (OS) was 62.8 months in the standard arm and 54.4 months in the HD arm (HR, 1.17; 95% CI, 0.71 to 1.94; P, .54).ConclusionThis is the first randomized trial comparing sequential HD versus standard dose chemotherapy in first-line treatment of patients with advanced ovarian cancer. We observed no statistically significant difference in progression-free survival or OS and conclude that HD chemotherapy does not appear to be superior to conventional dose chemotherapy.

scholarly journals Changes in DNA Damage Response Markers with Treatment in Advanced Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 707 ◽  
Author(s):  
Paul Kubelac ◽  
Catherine Genestie ◽  
Aurelie Auguste ◽  
Soizick Mesnage ◽  
Audrey Le Formal ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Excision Repair ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Similar Proportion ◽  
End Joining ◽  
Dismal Prognosis ◽  
Base Excision ◽  
Non Homologous End Joining

Ovarian cancer (OC) is sensitive to upfront chemotherapy, which is likely attributable to defects in DNA damage repair (DDR). Unfortunately, patients relapse and the evolution of DDR competency are poorly described. We examined the expression of proposed effectors in homologous recombination (HR: RAD51, ATM, FANCD2), error-prone non-homologous end-joining (NHEJ: 53BP1), and base excision repair pathways (BER: PAR and PARP1) in a cohort of sequential OC samples obtained at diagnosis, after neoadjuvant chemotherapy (NACT), and/or at relapse from a total of 147 patients. Immunohistochemical (IHC) expression was quantified using the H-score (0–300), where H ≤ 10 defined negativity. Before NACT, a significant number of cases lacked the expression of some effectors: 60%, 60%, and 24% were PAR-, FANCD2-, or RAD51-negative, with a reassuringly similar proportion of negative biomarkers after NACT. In multivariate analysis, there was a poorer progression-free survival (PFS) and overall survival (OS) for cases with competent HR at diagnosis (PRE-NACT 53BP1−/RAD51+, hazard ratio (HR) 3.13, p = 0.009 and HR 2.78, p = 0.024) and after NACT (POST-NACT FANCD2+/RAD51+ HR 1.89, p = 0.05 and HR 2.38, p = 0.02; POST-NACT PARP-1+/RAD51+ HR 1.79, p = 0.038 and HR 2.04, p = 0.034), reflecting proficient DNA repair. Overall, HR-competent tumors appeared to have a dismal prognosis in comparison with tumors utilizing NHEJ, as assessed either at baseline or post-NACT. Accurate knowledge of the HR status during treatment is clinically important for the efficient timing of platinum-based and targeted therapies with poly(ADP-ribose) polymerase inhibitors (PARPi).

scholarly journals Estimating long-term overall survival with olaparib as maintenance therapy in patients with newly diagnosed advanced ovarian cancer with BRCA mutations

2021 ◽  
Vol 17 (3) ◽  
pp. 97-105
Author(s):  
N. A. Avxentyev ◽  
S. V. Khokhlova ◽  
M. Yu. Frolov ◽  
A. S. Makarov
Keyword(s):  
Ovarian Cancer ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
First Line ◽  
Brca Mutations ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Line Chemotherapy

Background. According to randomized clinical trial SOLO1 olaparib statistically significantly improves progression-free survival versus placebo as a maintenance monotherapy in patients aged 18 and over with newly diagnosed advanced ovarian cancer with BRCA mutations, who had response to first-line chemotherapy. As the data on overall survival (OS) in this trial remains interim it is still uncertain whether treatment with olaparib can provide any benefits in terms of OS.Objective: to evaluate a long-term OS for olaparib versus placebo as a maintenance monotherapy in patients with newly diagnosed advanced ovarian cancer with BRCA mutations, who had response to first-line chemotherapy.Materials and methods. A 10-year mathematic model of disease progression and survival on olaparib versus placebo was developed. Modelling was based on data on progression-free survival from SOLO1 trial and data on OS after platinum-sensitive and platinum-resistant relapses from OCEANS and AURELIA trials. Additionally, patients who haven’t been treated with olaparib after first-line therapy in base-case scenario were assumed to get olaparib as a second-line treatment after platinum-sensitive relapse; mortality modelling for these patients was based on data from SOLO2 trial.Results. Median OS for olaparib was 107 months versus 66 months for placebo. 46 % of patients treated with olaparib were alive by the end of 10-year modelling period, but only 28 % patients from the placebo group. Hazard ratio of death for olaparib versus placebo was 0.64 (95 % confidence interval 0.49–0.84). Probabilistic sensitivity analysis showed robustness of these results.Conclusion. Using olaparib as a maintenance therapy in patients with newly diagnosed advanced ovarian cancer with BRCA mutations, who had response on first line chemotherapy, statistically significantly reduces risk of death by 36 %, compared to placebo.

scholarly journals FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1866
Author(s):  
Katia A. Mesquita ◽  
Reem Ali ◽  
Rachel Doherty ◽  
Michael S. Toss ◽  
Islam Miligy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
High Throughput Screening ◽  
Nuclear Translocation ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Progression Free Survival ◽  
Ovarian Cancer Cells ◽  
Physical Interaction ◽  
Base Excision

FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemotherapy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin β. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy.

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