Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial

Kristeleit, Rebecca; Lisyanskaya, Alla; Fedenko, Alexander N.; Dvorkin, Mikhail; Melo, Andréia Cristina de; Shparyk, Yaroslav; Rakhmatullina, Irina; Bondarenko, Igor; Colombo, Nicoletta; Svintsitskiy, V; Biela, Luciano; Nechaeva, Marina; Lorusso, Domenica; Scambia, Giovanni; Cibula, David; Póka, Ròbert; Oaknin, Ana; Safra, Tamar; Maćkowiak-Matejczyk, Beata; Ma, Ling; Thomas, Daleen; Lin, Kevin K.; McLachlan, Karen R.; Goble, Sandra; Oza, Amit M.

doi:10.1016/s1470-2045(22)00122-x

Cited by 93 publications

(79 citation statements)

References 24 publications

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“…The safety profile for rucaparib in ATHENA-MONO is consistent with that of rucaparib in other settings [13][14][15] and other PARP inhibitors in the first-line maintenance setting. 2,3,5 The most common nonhematologic TEAEs observed with rucaparib were generally low grade, and the majority of grade $ 3 events were hematologic TEAEs previously associated with PARP inhibitors.…”

Section: Discussionsupporting

confidence: 67%

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45)

Monk

Parkinson

Lim

et al. 2022

JCO

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204

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PURPOSE ATHENA (ClinicalTrials.gov identifier: NCT03522246 ) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA–MONO comparison of rucaparib versus placebo. METHODS Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD.

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Section: Discussionsupporting

confidence: 67%

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45)

Monk

Parkinson

Lim

et al. 2022

JCO

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204

116

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“…The investigator-assessed median PFS in the efficacy population was 7.4 months (95% CI, 7.3-9.1) with rucaparib in comparison with 5.7 months (95% CI, 5.5-7.3) with chemotherapy (HR, 0.64; 95% CI, 0.49-0.84; P = 0.001). In the ITT population, the median PFS wasthesameat7.4months(95%CI,6.7-7.9) and 5.7 months (95% CI, 5.5-6.7) in the rucaparib and chemotherapy arms, respectively, but showed a hazard ratio of 0.67 (95% CI, 0.52-0.86; P = 0.0017) [37]. As of June 2022, the manufacturer of rucaparib, Clovis has released a Dear HCP Letter informing HCPs that they have voluntarily withdrawn rucaparib's late line treatment indication in consultation with FDA after a detrimental effect of OS was observed for rucaparib compared to the chemotherapy control arm in the ARIEL-4 trial.…”

Section: Treatment Of Recurrent Epithelial Ovarian Cancermentioning

confidence: 98%

PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer

Santo¹,

Bagnolini²,

Wong³

et al. 2023

Recent Advances, New Perspectives and Applications in the Treatment of Ovarian Cancer

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Epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy in the western world, has been historically treated with surgery followed by chemotherapy. Poly (ADP-ribose) polymerase (PARP) inhibitors are one of the most active new targeted therapies for the treatment of EOC. PARPis’ mechanism of action relies on their ability to interfere with DNA repair events leading ultimately to cell death, the biological concept known as synthetic lethality. Initially developed as maintenance therapy in patients with a response after platinum-based chemotherapy in a recurrent setting, PARPis are now approved as the frontline treatment strategy. The aim of this chapter is to examine PARPis’ antineoplastic activity and the clinical development studies that lead to their approval, as well as the safety and the management of adverse events associated with this new class of drugs. Lastly, the rational considerations for the use of PARPis in the frontline setting are discussed.

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“…Severe adverse events were also studied, with notable mentions of anaemia and elevated transaminases with 18.8% and 10.5%, respectively [ 46 ]. In the ARIEL4 study (NCT02855944), the efficacy and safety of rucaparib in relapsing EOC in patients with BRCA -mutated genes are being investigated when compared with standard chemotherapy [ 47 ]. In the efficacy population (220 patients in the rucaparib group; 105 in the chemotherapy group), the median PFS was 7.4 months (95% CI 7.3–9.1) in the rucaparib group versus 5.7 months (5.5–7.3) in the chemotherapy group (HR 0.64; 95% CI 0.49–0.84; p = 0.0010).…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer

Revythis

Limbu

Mikropoulos

et al. 2022

IJERPH

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Ovarian cancer is one of the most common gynecologic cancers and has the highest mortality rate of any other cancer of the female reproductive system. Epithelial ovarian cancer (EOC) accounts for approximately 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery accompanied by pre- or postoperative platinum-based chemotherapy. Nevertheless, up to 80% of the patients relapse within the following 12–18 months from the completion of the treatment and then receive first-line chemotherapy depending on platinum sensitivity. Mutations in BRCA1/2 genes are the most significant molecular aberrations in EOC and serve as prognostic and predictive biomarkers. Poly ADP-ribose polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality. They have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. Olaparib, rucaparib, and niraparib have all obtained Food and Drug Administration (FDA) and/or the European Medicine Agency (EMA) approval for the treatment of EOC in different settings. Immune checkpoint inhibitors (ICI) have improved the survival of several cancers and are under evaluation in EOC. However, despite the success of immunotherapy in other malignancies, the use of antibodies inhibiting the immune checkpoint programmed cell death (PD-1) or its ligand (PD-L1) obtained modest results in EOC so far, with median response rates of up to 10%. As such, ICI have not yet been approved for the treatment of EOC. We herein provided a comprehensive insight into the most recent progress in synthetic lethality PARP inhibitors, along with the mechanisms of resistance. We also summarised data regarding the role of immune checkpoint inhibitors, the use of vaccination therapy, and adoptive immunotherapy in treating epithelial ovarian cancer.

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Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4): an international, open-label, randomised, phase 3 trial

Cited by 93 publications

References 24 publications

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45)

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45)

PARP Inhibitors in the Treatment of Epithelial Ovarian Cancer

Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer

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