PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

Evans, Tarra; Matulonis, Ursula A.

doi:10.1177/1758834016687254

Cited by 85 publications

(86 citation statements)

References 59 publications

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“…Poly (ADP) ribose polymerase inhibitors have been intentionally designed to target BRCA1/2-deficient tumor cells; as expected, their activity demonstrates some overlap with platinum compounds. 33 In addition, BRCA1/2-driven tumors, being genetically unstable, produce increased number of tumor antigens. Some data indicate that the use of immune checkpoint modulators may further improve the results of the treatment of cancers arising in BRCA1/2 mutation carriers.…”

Section: Discussionmentioning

confidence: 99%

Atl

Gorodnova

Kotiv

Ivantsov

et al. 2018

Int J Gynecol Cancer

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ObjectivesCisplatin and mitomycin C exert high activity towards BRCA1-deficient cells. This study aimed to evaluate the efficacy of a combination of these drugs in hereditary BRCA1-associated ovarian cancer (OC).MethodsTwelve OC patients, who could not be treated by primary debulking surgery owing to extensive tumor spread, were given neoadjuvant cisplatin (100 mg/m2) and mitomycin C (10 mg/m2) every 4 weeks for 3 (n = 9), 2 (n = 2), or 4 (n = 1) cycles.ResultsThe decrease of tumor burden and complete surgical cytoreduction were achieved in all patients. Pathologic complete response, defined as the absence of tumor cells in surgically removed tissues, was observed in 2 (17%) of 12 cases. Retrospective analysis of 62 OC in BRCA1 mutation carriers subjected to conventional neoadjuvant chemotherapy schemes revealed 36 objective tumor responses (58%) and 37 instances (60%) of complete cytoreductive surgery; however, none of these patients demonstrated pathologic complete response.ConclusionsThe combination of cisplatin plus mitomycin C showed promising results in BRCA1-driven OC and therefore deserves further clinical evaluation.

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Section: Discussionmentioning

confidence: 99%

Atl

Gorodnova

Kotiv

Ivantsov

et al. 2018

Int J Gynecol Cancer

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“…Moreover, studies suggested that PARP inhibitor BMN673 increased the proportion of cytotoxic immune cells while simultaneously decreasing the proportion of immunosuppressive cells in BRCA-deficient ovarian cancer mouse [101]. Based on the promising results, there are several ongoing trials combining PARP and immune checkpoint inhibitors [102].…”

Section: Targeted Therapymentioning

confidence: 99%

Complex interplay between tumor microenvironment and cancer therapy

Shen

Kang

2018

Front. Med.

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Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

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“…This alternative pathway activation increases the mutation rate and genomic instability. PARP-1 and PARP-2 are involved in DNA repair through binding to DNA single-strand breaks; this link creates a polymer that is recognized by protein involved in base excision repair (BER) pathway for repairing single strand breaks on DNA (Evans and Matulonis, 2017;Liu et al, 2017;Pulliam et al, 2018).…”

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confidence: 99%

The Era of PARP inhibitors in ovarian cancer: “Class Action” or not? A systematic review and meta-analysis

Staropoli

Ciliberto

Giudice

et al. 2018

Critical Reviews in Oncology/Hematology

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Introduction: Carboplatin is the milestone of epithelial ovarian cancer (EOC) treatment, thus response to platinum is the major prognostic factor. Among platinum-sensitive patients, 40% carry a germline or somatic BRCA1/2 mutation. In this scenario a new class of drugs, the PARP inhibitors (PARPis), produced a significant improvement in long-term disease control. In order to make an aggregate evaluation of the impact of these agents, we performed a systematic review and meta-analysis. Patients and Methods: Clinical trials were selected by searching "Pubmed" database and abstracts from major cancer meetings. We considered the January 2008-April 2018 time frame. Progression free survival (PFS) was the primary end-point, toxicities were secondary end-points. Hazard ratios (HRs) of PFS, with confidence intervals, and risk ratios of grade 3-4 toxicity rates, were extracted from retrieved studies and included in the current analysis. Meta-analysis was carried out by the fixed and random effect models. We conducted this metaanalysis to also compare indirectly the efficacy of different PARPis in EOC patients. Results: Five randomized trials for a total of 1839 patients were selected and included in the final analysis. In particular, we evaluated a BRCA-mutant cohort (871 patients) with a pooled HR 0.25 (95%CI 0.21-0.31) and the BRCA-wild type cohort (836 patients) with a pooled HR 0.41 (95%CI 0.31-0.55), respectively. Regarding safety profile, no significant differences were detected in all grade toxicities, however, taking into account 3-4 grade toxicities and SAEs (severe adverse events), we show that rucaparib-treated patients reported major abdominal pain events, while niraparib-treated patients were associated with the highest percentage of haematological toxicities, hypothesizing a drug effect for the safety analysis. In the indirect comparisons, significant differences were not detected on PFS for the different agents. Conclusions: We confirm a significant benefit in survival outcome of PARPis for EOC patients with a "class effect" on the bases of narrow CI and indirect comparisons in the different groups. Therefore, we underline that this strategy is of special value in BRCA-mutated patients because genetic testing allows best patient selection for all PARPis with the added value of individualized prevention in familiars. 1. Background Among epithelial ovarian cancer (EOC) patients, women with genetic predisposition show an early onset of disease. Rare high penetrant mutations in BRCA1 and BRCA2 genes greatly increase lifetime risk and account for the majority of hereditary cases, 10%-15% of all cases. These women have a 40-60% lifetime risk of EOC (44% in BRCA1 families and 27% in BRCA2 families, respectively) (Mavaddat et al., 2012; Xu et al., 2017). The gold standard first-line treatment is still based on the combination of carboplatin/paclitaxel (du Bois et al., 1997; Jayson et al., 2014). The management of recurrent disease strictly depends on

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PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

Cited by 85 publications

References 59 publications

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Complex interplay between tumor microenvironment and cancer therapy

The Era of PARP inhibitors in ovarian cancer: “Class Action” or not? A systematic review and meta-analysis

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