Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis

Poveda, Andrés; Lheureux, Stéphanie; Colombo, Nicoletta; Cibula, David; Lindemann, Kristina; Weberpals, Johanne I.; Bjurberg, Maria; Oaknin, Ana; Sikorska, M.; González-Martín, Antonio; Mądry, Radosław; Pérez, María Jesús Rubio; Ledermann, Jonathan A.; Davidson, Richard; Blakeley, C.; Bennett, James; Barnicle, Alan; Škof, Erik

doi:10.1016/j.ygyno.2021.12.025

Cited by 33 publications

(26 citation statements)

References 22 publications

(55 reference statements)

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“…Therefore, exploring a reliable and unified biomarker detection method to screen patients and select appropriate PARPi is demanded ( Xu and Li, 2021 ). In the phase IIIb OPINION trial (NCT03402841) ( Poveda et al, 2022 ), maintenance olaparib demonstrated clinical benefit in patients without a germline BRCA1/BRCA2 mutation (gBRCAm). Additionally, the phase Ⅲ trial L-MOCA (NCT03534453) ( Gao et al, 2022 ), focused on olaparib maintenance monotherapy in Asian patients with platinum-sensitive relapsed (PSR) ovarian cancer has been published this year.…”

Section: Current Approved Parp Inhibitorsmentioning

confidence: 99%

Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305

Zheng

Min

2023

Front. Pharmacol.

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The family of poly (ADP-ribose) polymerases (PARPs) consists of 17 members, which have been demonstrated as having effects on a series of cellular processes, including DNA replication and repair. PARP inhibitors (PARPi) suppress DNA repair through “PARP trapping”, thus, constitute an important treatment option for cancer nowadays. In addition, PARP inhibition and homologous recombination repair (HRR) defects are synthetically lethal, giving a promising therapeutic for homologous recombination repair deficient (HRD) tumors including BRCA mutation. However, overlapping hematologic toxicity causes PARPi to fail in combination with some first-line chemotherapies. Furthermore, recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for antitumor activity in HRD cancer models. Currently approved PARPi have shown varying levels of selectivity for the entire 17-member PARP family, hence contribute to toxicity. Together, these findings above have provided the necessity and feasibility of developing next-generation PARPi with improved selectivity for PARP1, expanding significant clinical values and wide application prospects both in monotherapy and combination with other anticancer agents. In this review, we summery the latest research of current approved PARPi, discuss the current status and future promise of next-generation PARP1-selective inhibitor AZD5305, including its reported progress up to now and anticipated impact on clinical.

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Section: Current Approved Parp Inhibitorsmentioning

confidence: 99%

Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305

Zheng

Min

2023

Front. Pharmacol.

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“…These results were confirmed in the phase 3 trial SOLO2, including only the BRCA mutant population, which showed a median PFS (mPFS) of 19.1 months in the olaparib arm versus 5.5 months with placebo arm [ 8 ]. Later, PFS results from large phase III/IV trials (NOVA/ENGOT-OV16 [ 9 ], ARIEL3 [ 10 ], OPINION [ 11 ], ORZORA [ 12 ]) supported further indications of niraparib, rucaparib, and olaparib as maintenance therapy after platinum used in the platinum-sensitive relapsed setting regardless of molecular status. Importantly, overall, these trials showed that the magnitude of benefit from PARPi after response to platinum-based chemotherapy differs among BRCA-mutant, HR-deficient or HR-proficient populations [ 13 ].…”

Section: Introductionmentioning

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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“…The four most commonly observed AEs in olaparibtreated patients in our study (anaemia, nausea, fatigue/ asthenia and decreased appetite) have also been reported as among the most commonly observed AEs in studies of olaparib in other tumour types, including breast [9e11], ovarian [12e17], and pancreatic cancers [18]. For example, the incidence of anaemia was 23% in the Study 19 ovarian cancer study [12], 27% in the POLO pancreatic cancer study [18], 40% in the OlympiAD breast cancer study [10] and 39%, 44%, 51% and 39% in the SOLO1 [13], SOLO2 [14], SOLO3 [15] and OPINION [16] ovarian cancer studies, respectively. The incidence we report for the PROfound study was 50%, although it should be noted that anaemia AEs reported were sometimes based on grouped terms which can differ between studies, hence comparing incidences of anaemia between studies can be unreliable.…”

Section: Discussionmentioning

confidence: 99%

Olaparib tolerability and common adverse-event management in patients with metastatic castration-resistant prostate cancer: Further analyses from the PROfound study

Roubaud

Özgüroǧlu

Penel

et al. 2022

European Journal of Cancer

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Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis

Cited by 33 publications

References 22 publications

Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305

Current status and future promise of next-generation poly (ADP-Ribose) polymerase 1-selective inhibitor AZD5305

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

Olaparib tolerability and common adverse-event management in patients with metastatic castration-resistant prostate cancer: Further analyses from the PROfound study

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