Maintenance therapies in metastatic pancreatic cancer: present and future with a focus on PARP inhibitors

Hammel, Pascal; Vitellius, Carole; Boisteau, Émeric; Wisniewski, Mathilde; Colle, Elise; Hilmi, Marc; d’Engremont, Christelle; Granier, Sandra; Turpin, Anthony; Mestier, Louis de; Neuzillet, Cindy

doi:10.1177/1758835920937949

Cited by 16 publications

(22 citation statements)

References 48 publications

(85 reference statements)

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“…25 Active maintenance therapy after cessation of initial treatment aims to extend PFS and overall survival (OS) without compromising health-related quality of life (HRQoL). [26][27][28][29][30] A significant PFS benefit was demonstrated in POLO for active maintenance olaparib versus placebo (median PFS by blinded independent central review [BICR]: 7.4 months v 3.8 months; hazard ratio [HR], 0.53; 95% CI, 0.35 to 0.82; P 5 .004). 25 The incidence of grade 3 or higher adverse events (AEs) was similar to that observed among patients receiving olaparib for the treatment of other tumor types.…”

Section: Introductionmentioning

confidence: 99%

Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Kindler

Hammel

Reni

et al. 2022

JCO

Self Cite

102

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PURPOSE The phase III POLO study demonstrated significant progression-free survival (PFS) benefit for active olaparib maintenance therapy versus placebo for patients with metastatic pancreatic adenocarcinoma and a germline BRCA mutation. Here, we report the final analysis of overall survival (OS) and other secondary end points. PATIENTS AND METHODS Patients with a deleterious or suspected deleterious germline BRCA mutation whose disease had not progressed after ≥ 16 weeks of first-line platinum-based chemotherapy were randomly assigned 3:2 to active maintenance olaparib (300 mg twice daily) or placebo. The primary end point was PFS; secondary end points included OS, time to second disease progression or death, time to first and second subsequent cancer therapies or death, time to discontinuation of study treatment or death, and safety and tolerability. RESULTS In total, 154 patients were randomly assigned (olaparib, n = 92; placebo, n = 62). No statistically significant OS benefit was observed (median 19.0 v 19.2 months; hazard ratio [HR], 0.83; 95% CI, 0.56 to 1.22; P = .3487). Kaplan-Meier OS curves separated at approximately 24 months, and the estimated 3-year survival after random assignment was 33.9% versus 17.8%, respectively. Median time to first subsequent cancer therapy or death (HR, 0.44; 95% CI, 0.30 to 0.66; P < .0001), time to second subsequent cancer therapy or death (HR, 0.61; 95% CI, 0.42 to 0.89; P = .0111), and time to discontinuation of study treatment or death (HR, 0.43; 95% CI, 0.29 to 0.63; P < .0001) significantly favored olaparib. The HR for second disease progression or death favored olaparib without reaching statistical significance (HR, 0.66; 95% CI, 0.43 to 1.02; P = .0613). Olaparib was well tolerated with no new safety signals. CONCLUSION Although no statistically significant OS benefit was observed, the HR numerically favored olaparib, which also conferred clinically meaningful benefits including increased time off chemotherapy and long-term survival in a subset of patients.

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Section: Introductionmentioning

confidence: 99%

Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Kindler

Hammel

Reni

et al. 2022

JCO

Self Cite

102

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“…In addition, the PRODIGE 4/ACCORD 11 trial recommended a total of 6 mo of palliative chemotherapy[ 10 ], therefore, the duration of therapy of 1 st line PtCh may not be out of keeping with other clinical trials in this setting of disease. Furthermore, use of placebo alone in the control group has come under criticism as evidence has emerged in favour of the continuation of 5-FU as maintenance therapy in patients who respond to FOLFIRINOX[ 75 ]. That being said, the accumulating side effects of > 4 mo of FOLFIRINOX may justify a treatment break, especially if there is no evidence of progression on imaging.…”

Section: Management Of Brca-mutated Pdac: Systemic Therapymentioning

confidence: 99%

BRCA mutated pancreatic cancer: A change is coming

Rosen

Goodwin

Vickers

2021

WJG

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Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease. Recently, patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors. Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8% of patients with sporadic pancreatic cancer. In patients with germline BRCA mutations, platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors are effective treatment options which may offer survival benefits. This review will focus on the molecular biology, epidemiology, and management of BRCA -mutated pancreatic cancer. Furthermore, we will discuss future directions for this area of research and promising active areas of research.

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“…Indeed, BRCA 1/2 are involved in homologous recombination repairs of double strand breaks together with other proteins such as PALB2, ATM, and RAD50 [ 120 ]. Therefore, it is not surprising that up to 17.4% of PDAC is characterized by “BRCAness” signature genes which imply the use of olaparib in presence of BRCA mutations [ 121 ].…”

Section: Genetic and Molecular Features Of Pdac Variantsmentioning

confidence: 99%

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

Bazzichetto

Luchini

Cognetti

et al. 2020

IJMS

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To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.

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Maintenance therapies in metastatic pancreatic cancer: present and future with a focus on PARP inhibitors

Cited by 16 publications

References 48 publications

Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer

BRCA mutated pancreatic cancer: A change is coming

Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology

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