Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial

Frenel, Jean‐Sébastien; Kim, J W; Aryal, Nanda; Asher, Rebecca; Berton, Dominique; Vidal, Laura; Pautier, Patricia; Ledermann, Jonathan A.; Penson, Richard T.; Oza, A.M.; Korach, Jacob; Huzarski, Tomasz; Pignata, Sandro; Colombo, Nicoletta; Park-Simon, Tjoung Won; Tamura, Kenji; Sonke, Gabe S.; Freimund, Alison; Lee, C K; Pujade-Lauraine, Éric

doi:10.1016/j.annonc.2022.06.011

Cited by 87 publications

(48 citation statements)

References 22 publications

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“…The 5 months of progression-free survival found in our series is shorter than what we would expect in a platinum-sensitive population. However, our data are in line with others recently published8–20 according to which, following progression from maintenance PARP inhibitors in the recurrent setting, the efficacy of subsequent platinum-based chemotherapy seems to be reduced. Therefore, we further confirm that progression while on PARP inhibitors is challenging to treat.…”

Section: Discussionsupporting

confidence: 92%

Trabectedin plus pegylated liposomal doxorubicin in patients with disease progression after PARP inhibitor maintenance: a real-life case–control study

Vertechy

Boccia

Tiberi

et al. 2022

Int J Gynecol Cancer

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ObjectivePoly (ADP-ribose) polymerase (PARP) inhibitor resistance is problematic in epithelial ovarian cancer management and sequencing strategies may be performed to overcome this issue. In this context, our study evaluated the role of non-platinum doublet pegylated liposomal doxorubicin/trabectedin in ovarian cancer platinum-sensitive patients who experienced disease progression under PARP inhibitor maintenance.MethodsThis case–control study includes patients with recurrent epithelial ovarian cancer treated between March 2016 and April 2021 who progressed under PARP inhibitor maintenance. Data of patients treated with pegylated liposomal doxorubicin/trabectedin (experimental group) were matched 1:1 with a series of patients who received platinum-based treatment (control group). The study outcomes were overall clinical benefit (including complete, partial, and stable response), progression-free survival, and overall survival. The safety of both treatments was also evaluated.ResultsA total of 26 patients in both groups were analyzed. Clinical benefit was achieved in 15 (57%) patients in the study group and 17 (65%) patients in the control group (p=0.38). Patients receiving pegylated liposomal doxorubicin/trabectedin had 5 months of progression-free survival, compared with 5 months in patients treated with platinum-based treatment (p=0.62). Patients in the experimental group achieved a median overall survival of 16 months compared with 19 months in the control group (p=0.26) There was no difference concerning severe toxicities (G3-G4) between groups, except for hepatic toxicity, which was experienced in 30% of the patients receiving pegylated liposomal doxorubicin/trabectedin and none in the control group (p<0.009).ConclusionsPegylated liposomal doxorubicin/trabectedin might be an alternative option to platinum-based treatment in patients experiencing disease progression during PARP inhibitor maintenance with an acceptable toxicity profile. This might be a therapeutic option in this setting, sparing platinum compounds for subsequent relapse.

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Section: Discussionsupporting

confidence: 92%

Trabectedin plus pegylated liposomal doxorubicin in patients with disease progression after PARP inhibitor maintenance: a real-life case–control study

Vertechy

Boccia

Tiberi

et al. 2022

Int J Gynecol Cancer

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“…However, the first clinical evidence of a potential detrimental effect of PARPi on subsequent platinum-based chemotherapy came from a post-hoc analysis of SOLO2 trial communicated in ESMO congress 2020 by Frenel et al, including only BRCA1/2-mutant patients who had progressed to olaparib/placebo [ 28 ]. This work, very recently published, showed a longer time to second progression (TSP, measured from progression to olaparib/placebo to progression to subsequent chemotherapy line) among patients who had received placebo in comparison to those treated with olaparib, particularly when subsequent chemotherapy was platinum-based (14.3 months versus 7 months, n = 42 and 54, respectively) [ 29 ]. Additionally, little data is available from a post-hoc analysis of NOVA trial showing no differences of PFS2-PFS1 (defined as the time between progression to niraparib/placebo to the subsequent progression or death) between the placebo and niraparib arms [ 30 ], which could be consistent with a potential balanced effect between BRCA and non BRCA-mutant population.…”

Section: Discussionmentioning

confidence: 99%

Multicenter Real-World Data of Subsequent Chemotherapy after Progression to PARP Inhibitors in a Maintenance Relapse Setting

Romeo

Gil-Martín

Gaba

et al. 2022

Cancers

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Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included [46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes]. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval [PFI] was >6 months after the last cycle of prior platinum) [median PFI 12.0 months (interquartile range, IQR, 8.8–17.1)]. Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6–9.2), and median OS (mOS) of 20.6 months (95% CI 13.6–28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 [IQR11.2–22.2] and 10.3 [IQR 7.4–14.9] months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5–8.6) versus 7.5 months (95% CI 6.5–10.1, p = 0.03), and 16.4 (95% CI 9.3–27.5) versus 24.2 months (95% CI 17.2–NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients.

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“…In SOLO-2, a study in 2021 updated the median OS prolongation by 12.9 months when reaching a median follow-up time of more than 5 years based on the previously reported significant prolongation of the mPFS in the olaparib group compared to the placebo group (Hutchinson, 2017;Francis et al, 2022), and the olaparib maintenance phase would not have a negative impact on health-related quality of life (HRQOL) (Friedlander et al, 2018); this study supports the benefit of maintenance treatment with olaparib in patients with PSROC with BRCA1/2 mutations. Based on data provided by SOLO2, Frenel et al evaluated the time to second progression (TTSP) from RECIST progression to the next progression/death in placebo-treated and olaparib-treated cohorts of patients who received non-platinum and platinum-based chemotherapy, respectively, and they found that when second-line olaparib was maintained for reprogression, patients with recurrent BRCA1/2mutant PSROC had weaker efficacy when platinum-containing chemotherapy was reapplied than patients who had not previously used PARPis (Frenel et al, 2022). Francis et al found that dose changes within the first 12 weeks of treatment did not impact survival outcomes, suggesting that in clinical practice, patients who had olaparib reduced or even discontinued due to AE intolerance would not experience an impact on PFS and OS (Domchek et al, 2016).…”

Section: Second-line and Beyond Treatment With Olaparibmentioning

confidence: 99%

Targeted therapy and immunotherapy: Diamonds in the rough in the treatment of epithelial ovarian cancer

Huang

Shan

et al. 2023

Front. Pharmacol.

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Currently, for ovarian cancer, which has the highest mortality rate among all gynecological cancers, the standard treatment protocol is initial tumor cytoreductive surgery followed by platinum-based combination chemotherapy. Although the survival rate after standard treatment has improved, the therapeutic effect of traditional chemotherapy is very limited due to problems such as resistance to platinum-based drugs and recurrence. With the advent of the precision medicine era, molecular targeted therapy has gradually entered clinicians’ view, and individualized precision therapy has been realized, surpassing the limitations of traditional therapy. The detection of genetic mutations affecting treatment, especially breast cancer susceptibility gene (BRCA) mutations and mutations of other homologous recombination repair defect (HRD) genes, can guide the targeted drug treatment of patients, effectively improve the treatment effect and achieve a better patient prognosis. This article reviews different sites and pathways of targeted therapy, including angiogenesis, cell cycle and DNA repair, and immune and metabolic pathways, and the latest research progress from preclinical and clinical trials related to ovarian cancer therapy.

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Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial

Cited by 87 publications

References 22 publications

Trabectedin plus pegylated liposomal doxorubicin in patients with disease progression after PARP inhibitor maintenance: a real-life case–control study

Trabectedin plus pegylated liposomal doxorubicin in patients with disease progression after PARP inhibitor maintenance: a real-life case–control study

Multicenter Real-World Data of Subsequent Chemotherapy after Progression to PARP Inhibitors in a Maintenance Relapse Setting

Targeted therapy and immunotherapy: Diamonds in the rough in the treatment of epithelial ovarian cancer

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