Phase III trial of lurbinectedin versus PLD or topotecan in platinum-resistant ovarian cancer patients: Results of CORAIL trial

Gaillard, Stéphanie; Oaknin, Ana; Vergote, Ignace; Scambia, Giovanni; Colombo, Nicoletta; Ghamande, Sharad; Soto-Matos, Arturo; Fernández, Cristian; Kahatt, Carmen; Gómez, Javier; Nieto, Antonio; Torres, Nicolás; Pardo-Burdalo, Beatriz; Pápai, Zsuzsanna; Kristeleit, RS; O’Malley, David M.; Benjamin, Ivy; Pautier, Patricia; Lorusso, Domenica

doi:10.1093/annonc/mdy285

Cited by 15 publications

(18 citation statements)

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“…The recruitment process has been already completed but results are still pending. During ESMO 2018, PRIMA results of this Adverse Reactions (RADAR) analysis were presented [39]. In particular, 480 patients were treated with a fixed 300 mg starting dose of niraparib or placebo and 247 patients were treated with an individualized dose of niraparib or placebo based on weight and platelet count (200 mg for body weight < 77 kg and platelet count < 150,000 μL and 300 mg in all other patients).…”

Section: Niraparibmentioning

confidence: 99%

“…In another phase II study the combination of durvalumab and olaparib was tested in 34 ROC patients (6 gBRCAm and 28 BRCAwt) with platinum sensitive or resistant disease. The preliminary efficacy results, presented during the ESMO congress 2018, showed a response rate and DCR of 15% and 53%, respectively [55]. The combination of olaparib at a dose of 300 mg BID with tremelimumab, a CTLA-4 antibody, at a dose of 10 mg/kg monthly, was tested in another phase I trial [55] for the treatment of BRCA 1/2m ROC and demonstrated good safety.…”

Section: Parpis and Immune Checkpoint Inhibitorsmentioning

confidence: 99%

“…The preliminary efficacy results, presented during the ESMO congress 2018, showed a response rate and DCR of 15% and 53%, respectively [55]. The combination of olaparib at a dose of 300 mg BID with tremelimumab, a CTLA-4 antibody, at a dose of 10 mg/kg monthly, was tested in another phase I trial [55] for the treatment of BRCA 1/2m ROC and demonstrated good safety. Several studies assessing the efficacy of PARPis in combination with immunotherapy are ongoing.…”

Section: Parpis and Immune Checkpoint Inhibitorsmentioning

confidence: 99%

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PARP inhibitors in ovarian cancer

Franzese

Centonze

Diana

et al. 2019

Cancer Treatment Reviews

170

132

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Poly-ADP-ribose polymerase inhibitors (PARPis) are the most active and interesting therapies approved for the treatment of epithelial ovarian cancer. They have changed the clinical management of a disease characterized, in almost half of cases, by extreme genetic complexity and alteration of DNA damage repair pathways, particularly homologous recombination (HR) deficiency. In this review, we provide an updated overview of the available results of recent clinical trials on the three Food and Drug Administration and European Medicines Agency approved PARPis in ovarian cancer: olaparib, niraparib, and rucaparib. Furthermore, we anticipate the future perspective of combination regimens with antiangiogenic, immunocheckpoint inhibitors, and other biological agents as strategies to overcome resistance mechanisms, potentiate the therapeutic efficacy, and expand their clinical use in non-HR deficient tumors. Mechanism of action of PARPs and PARPs inhibitors PARPs are a family of 17 nucleoproteins characterized by a common catalytic site that transfers an ADP-ribose group on a specific acceptor protein using NAD + as cofactor. Interestingly, most PARP members are able to transfer only a mono-ADP ribose group to their target proteins, whereas PARP1, PARP2, PARP3, PARP5a, PARP5b characteristically add repeated ADP-ribose units, thus generating long poly(ADP-ribose) (PAR) chains [5]. This post-translational protein modification is named PARylation and allows PARPs involvement in different cellular activities. In this regard, PARP1 is the best characterized PARP. PARP1 modulates chromatine structure via PARylation of core histone proteins resulting in chromatine relaxation, thus enabling replication, repair, and transcription processes [6]. As to transcription, PARP1 plays a pivotal role in its regulation by both serving as a transcriptional cofactor and by hindering methylation of specific sequences, like those of housekeeping genes (Fig. 1a/b). To date, activation of PARP-1, dependent on CCCTC binding factor (CTCF), appears to affect DNA

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Section: Niraparibmentioning

confidence: 99%

Section: Parpis and Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Section: Parpis and Immune Checkpoint Inhibitorsmentioning

confidence: 99%

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PARP inhibitors in ovarian cancer

Franzese

Centonze

Diana

et al. 2019

Cancer Treatment Reviews

170

132

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“…23 In 20 patients with platinum-sensitive disease, the ORR was 40%, and was 16.7% among 18 patients with platinum-resistant disease. 23 In 20 patients with platinum-sensitive disease, the ORR was 40%, and was 16.7% among 18 patients with platinum-resistant disease.…”

Section: Combination Of Cpis With Antiangiogenic Therapymentioning

confidence: 94%

“…At the European Society for Medical Oncology 2018 Congress, held October 19 to 23, 2018, in Munich, Germany, Liu et al presented a phase 2 trial of the combination of nivolumab at a flat dose of 240 mg and bevacizumab at a dose of 10 mg/kg every 2 weeks until disease progression that included 38 patients with recurrent ovarian cancer. 23 In 20 patients with platinum-sensitive disease, the ORR was 40%, and was 16.7% among 18 patients with platinum-resistant disease. Durable responses or prolonged stable disease were observed, even among patients with platinum-resistant disease.…”

Section: Combination Of Cpis With Antiangiogenic Therapymentioning

confidence: 94%

Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

González-Martín

Sánchez-Lorenzo

2019

Cancer

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Despite advances in surgery and chemotherapy and the integration of antivascular endothelial growth factor therapy as well as poly(adenosine diphosphate-ribose) polymerase inhibitors into daily clinical practice, epithelial ovarian cancer remains the leading cause of death from gynecological cancer. The incorporation of new therapies with the potential to achieve long-term disease remission is a clear need for patients with ovarian cancer. Immunotherapy with checkpoint inhibitors (CPIs) (antiprogrammed cell death protein 1 [anti-PD-1] or antiprogrammed death-ligand 1 [anti-PD-L1]) has been adopted in several malignancies based on improvements shown with regard to progression-free survival and in particular overall survival. Although there is a solid rationale for the use of CPIs in patients with ovarian cancer, to our knowledge the clinical data presented to date are not very convincing. This article reviews the current data regarding CPIs in patients with ovarian cancer along with the future directions and designs of clinical trials aiming to overcome the low efficacy of CPIs in these individuals. Cancer 2019;125:4616-4622.

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Dose exploration results from Phase 1 study of cemiplimab, a human monoclonal programmed death (PD)-1 antibody, in Japanese patients with advanced malignancies

Kitano¹,

Shimizu²,

Koyama³

et al. 2020

Cancer Chemother Pharmacol

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Purpose Part 1 of this two-part, open-label, Phase 1 study (NCT03233139) assessed the safety, tolerability, pharmacokinetics, immunogenicity, and clinical activity of cemiplimab in Japanese patients with advanced malignancies. Methods Patients received cemiplimab 250 mg (n = 6) or 350 mg (n = 7) every 3 weeks intravenously for up to 108 weeks in Part 1. Tumor responses were assessed by investigators every 9 weeks using the Response Evaluation Criteria in Solid Tumors version 1.1. Results Of 13 patients enrolled, median age was 62 years (range 33–75) and eight patients were female. Median duration of cemiplimab exposure was 13.1 weeks (range 3.0‒113.6). At the time of data cut-off, 11 patients (84.6%) had discontinued treatment (majority due to disease progression: n = 8, 61.5%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection (each n = 3, 23.1%). Five grade ≥ 3 TEAEs were reported in four patients: autoimmune colitis, dehydration, hyponatremia, hypophosphatemia, and muscular weakness. No dose-limiting toxicities were reported and no TEAEs led to death. Cemiplimab concentrations in serum were consistent with previously reported pharmacokinetic characteristics of cemiplimab. No anti-drug antibodies were detected in serum. Objective response rate [ORR; complete response + partial response (PR)] was 30.8% (four PR) and disease control rate [ORR + stable disease (SD)] was 46.2% (6/13; two SD). Conclusion Cemiplimab exhibited antitumor activity in Japanese patients with advanced malignancies. The safety profile was comparable to those previously reported for cemiplimab and other PD-1 inhibitors. Trial registration NCT03233139 at ClinicalTrials.gov. Graphic abstract

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Phase III trial of lurbinectedin versus PLD or topotecan in platinum-resistant ovarian cancer patients: Results of CORAIL trial

Cited by 15 publications

References 0 publications

PARP inhibitors in ovarian cancer

PARP inhibitors in ovarian cancer

Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

Dose exploration results from Phase 1 study of cemiplimab, a human monoclonal programmed death (PD)-1 antibody, in Japanese patients with advanced malignancies

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