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1.
Ann Oncol ; 34(2): 152-162, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36564284

RESUMEN

BACKGROUND: In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored. PATIENTS AND METHODS: Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD]. RESULTS: From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively. CONCLUSIONS: Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.


Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Humanos , Femenino , Bevacizumab/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteína BRCA1/genética , Ftalazinas/uso terapéutico , Mutación , Quimioterapia de Mantención , Proteína BRCA2/genética
2.
Ann Oncol ; 33(6): 593-601, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35219776

RESUMEN

BACKGROUND: Maintenance treatment with poly (ADP-ribose) polymerase (PARP) inhibitor is now the standard of care in patients with BRCA-mutated platinum-sensitive recurrent ovarian cancer following response to chemotherapy. In the SOLO2 trial, adverse event (AE)-associated olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients, respectively. We used data from the SOLO2 trial to evaluate the impact of dose alterations on survival outcomes and identified baseline characteristics associated with dose alteration. PATIENTS AND METHODS: We computed relative dose intensity (RDI) defined as the received dose as a percentage of the standard dose (300 mg twice a day) during the first 12 weeks on treatment. Patients were categorized into RDI >98%, RDI 90%-98%, and RDI <90%. The association between RDI categories with progression-free survival (PFS) and overall survival (OS) were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12 weeks. RESULTS: In patients on olaparib included in the landmark analysis (n = 185), the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90%-98% (n = 29), and <90% (n = 45) categories for PFS (median, 14.2 versus 19.3 versus 34.4 months; P = 0.37) and OS (median, 49.7 versus 49.5 versus 54.1 months; P = 0.84). Risk of RDI ≤90% increased with baseline performance status 1 [odds ratio (OR): 2.54; 95% confidence interval (CI): 1.11-5.82] any nausea (OR: 3.17; 95% CI: 0.9-11.23), and with body weight ≤70 kg (OR: 1.86; 95% CI: 0.92-3.76). CONCLUSIONS: Dose reduction and interruption for the management of olaparib-associated AEs during the first 12 weeks did not impact on PFS and OS. When counselling patients requiring dose reductions or interruptions due to AEs, the results of this study will help assure patients that their outcomes will not be adversely affected.


Asunto(s)
Reducción Gradual de Medicamentos , Neoplasias Ováricas , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Femenino , Humanos , Mutación , Recurrencia Local de Neoplasia/inducido químicamente , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Ftalazinas , Piperazinas , Poli(ADP-Ribosa) Polimerasas , Resultado del Tratamiento
3.
Clin Transl Oncol ; 23(5): 961-968, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33515422

RESUMEN

Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease.The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice.


Asunto(s)
Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/terapia , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Carcinoma Epitelial de Ovario/patología , Quimioterapia Adyuvante/métodos , Ensayos Clínicos Fase III como Asunto , Procedimientos Quirúrgicos de Citorreducción/métodos , Femenino , Humanos , Quimioterapia de Mantención/métodos , Oncología Médica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias/métodos , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sociedades Médicas , España
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