PARP inhibitors (PARPi) prolongation after local therapy for oligo-metastatic progression in relapsed ovarian cancer patients

Gauduchon, Thibault; Kfoury, Maria; Lorusso, Domenica; Floquet, Anne; Ventriglia, Jole; Salaün, Hélène; Moubarak, Malak; Rivoirard, Romain; Polastro, Laura; Favier, Laure; You, Benoît; Berton, Dominique; Rouge, Thibault De La Motte; Mansi, Laura; Abdeddaim, Cyril; Prulhière, Karine; Lecomte, Laurence; Provansal, Magali; Dalban, Cécile; Ray-Coquard, I. L.

doi:10.1016/j.ygyno.2023.04.002

Cited by 21 publications

(6 citation statements)

References 29 publications

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“…The median prolongation of the treatment-free interval in patients treated with surgery or stereotactic body radiotherapy was 6 and 10 months, respectively. Similar results were reported by Gauduchon et al 34 who evaluated the survival benefit of PARPi continuation or reintroduction in 74 patients with oligometastatic progression treated with local therapy and suggested the feasibility and potential benefit of this strategy with almost one year without progression or initiation of a new line of chemotherapy. However, these studies are retrospective and did not reach statistical significance.…”

Section: Potential De-escalation Strategies For the Recurrencesupporting

confidence: 85%

Systemic therapy de-escalation in advanced ovarian cancer: a new era on the horizon?

Caruso,

Coleman,

Aletti

et al. 2023

Int J Gynecol Cancer

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Poly(ADP-ribose) polymerase inhibitors (PARPi) have sculpted the current landscape of advanced ovarian cancer treatment. With the advent of targeted maintenance therapies, improved survival rates have led to a timely interest in exploring de-intensified strategies with the goal of improving quality of life without compromising oncologic outcomes. The emerging concept of systemic treatment de-escalation would represent a new frontier in personalizing therapy in ovarian cancer. PARPi are so effective that properly selected patients treated with these agents might require less chemotherapy to achieve the same oncologic outcomes. The fundamental key is to limit de-escalation to a narrow subpopulation with favorable prognostic factors, such as patients withBRCA-mutated and/or homologous recombination-deficient tumors without macroscopic residual disease after surgery or other high-risk clinical factors. Potential de-escalation strategies include shifting PARPi in the neoadjuvant setting, de-escalating adjuvant chemotherapy after primary debulking surgery, reducing PARPi maintenance therapy duration, starting PARPi directly after interval debulking surgery, omitting maintenance therapy, and continuing PARPi beyond oligoprogression (if combined with locoregional treatment). Several ongoing trials are currently investigating the feasibility and safety of de-escalating approaches in ovarian cancer and the results are eagerly awaited. This review aims to discuss the current trends, drawbacks, and future perspectives regarding systemic treatment de-escalation in advanced ovarian cancer.

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Section: Potential De-escalation Strategies For the Recurrencesupporting

confidence: 85%

Systemic therapy de-escalation in advanced ovarian cancer: a new era on the horizon?

Caruso,

Coleman,

Aletti

et al. 2023

Int J Gynecol Cancer

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“…Currently, there are a variety of possible approaches to a patient who progresses on or after PARP inhibitors [ 12 , 12 ]. Although a solid therapeutic algorithm is still missing, the use of loco-regional treatments such as surgical intervention or radiotherapy (RT) and the continuation of PARP inhibitors therapy is widely spread in oligo-metastatic progression, with data so far coming only from retrospective evidence alone [ 13 , 14 ]; therefore, the validation of this approach through a randomized prospective trial is needed.…”

Section: Discussionmentioning

confidence: 99%

MITO39: Efficacy and Tolerability of Pegylated Liposomal Doxorubicin (PLD)–Trabectedin in the Treatment of Relapsed Ovarian Cancer after Maintenance Therapy with PARP Inhibitors—A Multicenter Italian Trial in Ovarian Cancer Observational Case-Control Study

Turinetto,

Ricotti,

Marchetti

et al. 2023

Cancers

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Objective: While PLD-Trabectedin is an approved treatment for relapsed platinum-sensitive ovarian cancer, its efficacy and tolerability has so far not been tested extensively in patients who progress after poly ADP-ribose polymerase inhibitor (PARPi) treatment. Methodology: This multicenter, retrospective analysis had the objective of comparing patients receiving PLD-Trabectedin after being treated with PARP-I (cases) with PARPi-naïve patients. Descriptive and survival analyses were performed for each group. Results: Data from 166 patients were collected, composed of 109 cases and 57 controls. In total, 135 patients were included in our analyses, composing 46 controls and 89 cases. The median PFS was 11 months (95% IC 10–12) in the control group vs. 8 months (95% IC 6–9) in the case group (p value 0.0017). The clinical benefit rate was evaluated, with an HR for progression of 2.55 (1.28–5.06) for the case group (p value 0.008), persisting when adjusted for BRCA and line with treatment. We compared hematological toxicity, gastro-intestinal toxicity, hand–foot syndrome (HFS), fatigue, and liver toxicity, and no statistically significant disparity was noted, except for HFS with a p value of 0.006. The distribution of G3 and G4 toxicities was also equally represented. Conclusion: The MITO39 study showed a statistically significant difference in terms of PFS, suggesting that previous exposure to PARPi might inhibit the efficacy of PLD-Trabectedin. Regarding tolerability, no remarkable disparity was noted; PLD-Trabectedin was confirmed to be a well-tolerated scheme in both groups. To our knowledge, these are the first data regarding this topic, which we deem to be of great relevance in the current landscape.

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“…Recently, a retrospective analysis from Gauduchon et al. showed that PARPi prolongation after local therapy for oligometastatic progression offers 11.5 months of PFS ( 83 ). Palluzi et al.…”

Section: Overcoming Parp Inhibitor Resistance In the Setting Of ...mentioning

confidence: 99%

BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges

Collet,

Hanvic,

Turinetto

et al. 2024

Front. Oncol.

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BRCA1/2 genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of BRCA1/2 genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphosphate–ribose polymerase inhibitors (PARPi) have revolutionized the therapeutic landscape of BRCA1/2-mutated tumors, especially of BRCA1/2 high-grade serous ovarian cancer (HGSC), taking advantage of HR deficiency through the synthetic lethality concept. However, PARPi efficiency differs among patients, and most of them will develop resistance, particularly in the relapse setting. In the current proposal, we aim to review primary and secondary resistance to PARPi in HGSC owing to BRCA1/2 alterations. Of note, as several mechanisms of primary or secondary resistance to PARPi have been described, BRCA1/2 reversion mutations that restore HR pathways are by far the most reported. First, the type and location of the BRCA1/2 primary mutation have been associated with PARPi and platinum-salt sensitivity and impact the probability of the occurrence and the type of secondary reversion mutation. Furthermore, the presence of multiple reversion mutations and the variation of allelic frequency under treatment underline the role of intratumor heterogeneity (ITH) in treatment resistance. Of note, circulating tumor DNA might help us to detect and characterize reversion mutations and ITH to finally refine the treatment strategy. Importantly, forthcoming therapeutic strategies, including combination with antiangiogenics or with targeted therapies, may help us delay and overcome PARPi resistance secondary to BRCA1/2 reversion mutations. Also, progression despite PARPi therapy does not preclude PARPi rechallenge in selected patients.

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PARP inhibitors (PARPi) prolongation after local therapy for oligo-metastatic progression in relapsed ovarian cancer patients

Cited by 21 publications

References 29 publications

Systemic therapy de-escalation in advanced ovarian cancer: a new era on the horizon?

Systemic therapy de-escalation in advanced ovarian cancer: a new era on the horizon?

MITO39: Efficacy and Tolerability of Pegylated Liposomal Doxorubicin (PLD)–Trabectedin in the Treatment of Relapsed Ovarian Cancer after Maintenance Therapy with PARP Inhibitors—A Multicenter Italian Trial in Ovarian Cancer Observational Case-Control Study

BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges

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