Response to Chemotherapy and Clinical Outcome of Patients With Recurrent Epithelial Ovarian Cancer After PARP Inhibitor Maintenance Treatment: A Multicenter Retrospective Italian Study

Gadducci, Angiolo; Cosio, Stefania; Landoni, F; Lissoni, Andrea Alberto; Zola, Paolo; Laudani, Maria Elena; Ardizzoia, Antonio; Gambino, Angela; Sartori, Enrico

doi:10.21873/anticanres.15681

Cited by 15 publications

(10 citation statements)

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“…mOS for these subgroups were 8.9, 17.5, and 24.1 months, respectively. Our mOS regardless of BRCA status are consistent with these results [ 32 ].…”

Section: Discussionsupporting

confidence: 91%

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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“…mOS for these subgroups were 8.9, 17.5, and 24.1 months, respectively. Our mOS regardless of BRCA status are consistent with these results [ 32 ].…”

Section: Discussionsupporting

confidence: 91%

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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“…Recently, PARP inhibitors have been introduced as maintenance therapy for platinum-sensitive recurrent ovarian cancer, although reports on the treatment of recurrence during maintenance therapy are limited. Some studies report that platinum-based chemotherapy for platinum-sensitive recurrent ovarian cancer during PARP inhibitor treatment has a poor RR and short PFS (9)(10)(11)(12). In the present study, we aimed to examine the benefit of adding BEV to platinumbased chemotherapy for these patients.…”

Section: Discussionmentioning

confidence: 99%

“…However, reports on the treatment of recurrence after maintenance therapy are limited. Platinumbased chemotherapy for platinum-sensitive recurrence during PARP inhibitor treatment has been reported to result in a poor response rate (RR) and short progression-free survival (PFS) (9)(10)(11)(12). At our Institution, bevacizumab (BEV) is used in platinum-based chemotherapy for platinum-sensitive recurrent cancers.…”

mentioning

confidence: 99%

Efficacy and Safety of Platinum-based Chemotherapy With Bevacizumab Followed by Bevacizumab Maintenance for Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer During PARP Inhibitor Therapy: A Multicenter Retrospective Study

Abe¹,

Shoji²,

CHIBA³

et al. 2023

Anticancer Res

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Background/Aim: In recent years, the usefulness of poly ADP-ribose polymerase (PARP) inhibitors as subsequent maintenance therapy with poly ADP-ribose polymerase (PARP) inhibitors has been reported. However, it has been reported shown that platinum-based chemotherapy has a low response rate and short progression-free survival for recurrent platinum-sensitive ovarian cancer during treatment with PARP inhibitor therapy. This retrospective study evaluated platinum-based chemotherapy with bevacizumab (BEV) followed by BEV maintenance in these recurrent patients. Patients and Methods: Efficacy and safety were evaluated in 23 patients with ovarian, fallopian tube, or primary peritoneal cancer diagnosed with platinum-sensitive recurrence during PARP inhibitor treatment (administered from April 2019 to December 2022). Platinum-based chemotherapy included either paclitaxel with carboplatin, paclitaxel with cisplatin, docetaxel with carboplatin, or doxorubicin with carboplatin. BEV was administered in combination with any of these chemotherapies agents. Chemotherapy was administered for 6 cycles and BEV was administered up to 21 cycles. Results: The median numbers of cycles of platinum-based chemotherapy and BEV administration were 6 and 8, respectively. Complete response was observed in four patients (17.4%), partial response in 15 (65.2%), stable disease in two (8.7%), and progressive disease in two (8.7%). Objective response and disease control rates were 82.6% and 91.3%, respectively. Grade 3 or higher hematological toxicity occurred in 8 patients, with leukopenia, neutropenia in 14, anemia in 5, and thrombocytopenia in 4. On the other hand, non-hematological toxicities included hypertension in three patients, proteinuria in two, constipation in one, and carboplatin hypersensitivity in four. Only one patient discontinued chemotherapy due to an adverse event of proteinuria. No treatment-related deaths occurred. Conclusion: Platinum-based chemotherapy with BEV followed by BEV maintenance for platinum-sensitive recurrence during PARP inhibitor treatment was shown to be efficacious and safe. This combination should be further evaluated in larger randomized clinical trials.The incidence of ovarian cancer is increasing yearly, and it is the third most common gynecological malignancy after cervical and endometrial cancer. In 2020, there were 21,750 estimated new diagnoses of ovarian cancer and 13,940 deaths due to the disease in the USA; deaths due to ovarian cancer were higher than those due to endometrial and cervical cancers (1). Paclitaxel and carboplatin (TC) therapy is the goldstandard chemotherapy regimen for epithelial ovarian, fallopian tube, or primary peritoneal carcinoma based on clinical studies, such as the GOG111, OV-10, GOG158, and AGO trials (2-5). Recently, the usefulness of subsequent maintenance therapy with poly ADP-ribose polymerase (PARP) inhibitors was reported (6-8), and they have been adopted and widely used in 1265

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“…Better outcomes were seen in patients with a platinum-free interval (PFI) greater than 12 months. 16 PARPis re-exposure was prospectively investigated for the first time in the phase IIIb OReO/ ENGOT Ov-38 trial (NCT03106987). This study included women with recurrent platinumsensitive EOC who must had have responded to their most recent platinum regimen and received a prior course of maintenance PARPi.…”

Section: Fighting Resistance: Post-parp Inhibitor Treatment Strategie...mentioning

confidence: 99%

“…Better outcomes were seen in patients with a platinum-free interval (PFI) greater than 12 months. 16…”

Section: Introductionmentioning

confidence: 99%

Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer

et al. 2023

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Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a therapeutic milestone in the management of epithelial ovarian cancer. The concept of ‘synthetic lethality’ is exploited by PARPi in tumors with defects in DNA repair pathways, particularly homologous recombination deficiency. The use of PARPis has been increasing since its approval as maintenance therapy, particularly in the first-line setting. Therefore, resistance to PARPi is an emerging issue in clinical practice. It brings an urgent need to elucidate and identify the mechanisms of PARPi resistance. Ongoing studies address this challenge and investigate potential therapeutic strategies to prevent, overcome, or re-sensitize tumor cells to PARPi. This review aims to summarize the mechanisms of resistance to PARPi, discuss emerging strategies to treat patients post-PARPi progression, and discuss potential biomarkers of resistance.

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Response to Chemotherapy and Clinical Outcome of Patients With Recurrent Epithelial Ovarian Cancer After PARP Inhibitor Maintenance Treatment: A Multicenter Retrospective Italian Study

Cited by 15 publications

References 0 publications

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

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

Efficacy and Safety of Platinum-based Chemotherapy With Bevacizumab Followed by Bevacizumab Maintenance for Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer During PARP Inhibitor Therapy: A Multicenter Retrospective Study

Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer

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