Real-world clinical practice: Toxicities of maintenance PARP inhibitors in recurrent ovarian cancer—The Royal Marsden experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18770-e18770
Author(s):  
Zohra Ali ◽  
Laura Appadu ◽  
Ellen Kitetere ◽  
Julian Wampfler ◽  
Dorothy Yang ◽  
...  

e18770 Background: Maintenance therapy with PARP inhibitors (PARPi) in recurrent high grade ovarian cancer is standard of care for patients who have responded to second or subsequent lines of platinum-based chemotherapy. The increased access to PARP inhibitors (Olaparib, Niraparib and Rucaparib) has provided the opportunity to explore the real-world toxicities in routine clinical practice, toxicity management and the consequent impact on maintenance therapy outcomes. Methods: Patients with relapsed ovarian cancer that received maintenance PARP inhibitor therapy in routine clinical practice between April 2015 and April 2020 were identified. Electronic patient records were reviewed retrospectively to retrieve details of any reported toxicities (occurring at any time during therapy) and their management. Data was entered into and analysed in a Microsoft Excel spreadsheet. Results: 99 patients who received second or subsequent line maintenance PARPi therapy were included (median age 63.6 years). 36% had a germline BRCA1/2 mutation, 6% had a somatic BRCA1/2 mutation and 58% were BRCA wild-type. 69% received 2nd line maintenance therapy; 22% and 9% received a maintenance PARP inhibitor following 3rd or 4+ line therapy respectively. 56% had not received previous maintenance therapy; 43% had received Bevacizumab. 48% patients commenced maintenance therapy at full dose. 13% of patients experienced no toxicities. 60% of patients experienced G1-2 toxicities, with 42% experiencing >2 episodes; most common toxicities were fatigue, nausea/vomiting and thrombocytopenia. 26% of patients experienced >G3 toxicity, with 9% experiencing >2 episodes, 4% of which were recurring toxicities; most common toxicities were hypertension, neutropenia and anaemia. 64% of patients developed toxicity within the first cycle of treatment; 39% had a dose interruption, 56% of which were < 2 weeks duration. 59% patients required a dose reduction from their starting dose due to toxicities. There was no significant difference in median PFS between patients who had been dose reduced compared to those who received full starting dose (p > 0.05). Conclusions: In keeping with phase III clinical trials, our real-world experience is that most PARPi toxicities are low grade and occur early in treatment. Toxicities can be effectively managed with brief dose interruptions and dose reductions, without adverse impact on survival outcomes.

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e001110
Author(s):  
Susana Banerjee ◽  
Antonio Gonzalez-Martin ◽  
Philipp Harter ◽  
Domenica Lorusso ◽  
Kathleen N Moore ◽  
...  

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiency-positive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer.


Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5756
Author(s):  
Paul DiSilvestro ◽  
Nicoletta Colombo ◽  
Philipp Harter ◽  
Antonio González-Martín ◽  
Isabelle Ray-Coquard ◽  
...  

Recent data have demonstrated substantial efficacy with poly (ADP-ribose) polymerase (PARP) inhibitors as treatment and/or maintenance therapy in patients with newly diagnosed advanced epithelial ovarian cancer (EOC). Here, we review efficacy and safety results from four recent Phase III trials in newly diagnosed EOC: SOLO1 (olaparib), PAOLA-1 (olaparib in combination with bevacizumab), PRIMA (niraparib), and VELIA (veliparib). The implications of these data for current clinical practice and areas for future research are discussed, including ongoing studies of targeted agents in the newly diagnosed setting. Data from SOLO1, PAOLA-1, PRIMA, and VELIA confirm the benefit of PARP inhibitors (olaparib, niraparib, veliparib) for women with newly diagnosed EOC. The greatest benefit was seen in patients with a BRCA1 and/or BRCA2 mutation or in the homologous recombination deficiency (HRD)-test positive subgroup. These four well-conducted studies have generated practice-changing data. However, deciding how to apply these results in clinical practice is challenging, and substantial differences in trial design impede cross-trial comparisons. Recent PARP inhibitor approvals (olaparib, niraparib) in the newly diagnosed EOC setting have provided new maintenance treatment options for a broader patient population. The results of these studies call for personalized medicine based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. Important areas for future research include appropriate use of both BRCA mutation and HRD testing to inform magnitude of PARP inhibitor benefit as well as exploring further options for patients who are HRD-test negative and for those who become PARP inhibitor resistant.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5598-TPS5598 ◽  
Author(s):  
Philipp Harter ◽  
Mariusz Bidziński ◽  
Nicoletta Colombo ◽  
Anne Floquet ◽  
Maria Jesús Rubio Pérez ◽  
...  

TPS5598 Background: Ovarian cancer (OC) is the leading cause of death from gynecologic cancers in US women. Despite high response rates to first-line treatment, ~70% of patients (pts) relapse within 3 years and then remain largely incurable. First-line treatment needs to be improved to achieve long-term remission in pts and improve the cure rate. The Phase III SOLO1 trial showed a meaningful clinical benefit for olap maintenance therapy in newly diagnosed OC pts with a BRCA mutation (Moore et al N Engl J Med 2018). Preliminary data suggest that combining a PD-L1 inhibitor, anti-angiogenic and PARP inhibitor (triplet therapy) may achieve a synergistic antitumor effect. The DUO-O study (NCT03737643) evaluates the efficacy and safety of treatment combinations involving standard-of-care platinum-based chemotherapy (chemo), VEGF inhibitor bev, anti-PD-L1 antibody durva and PARP inhibitor olap, in women with newly diagnosed advanced OC. Methods: Eligible pts for this double-blind, randomized, Phase III study must have newly diagnosed, advanced, high-grade epithelial OC and either have completed primary surgery or plan to have interval debulking surgery. Depending on their tumor BRCA mutation (tBRCAm) status (determined by central test), pts will join one of two independent cohorts. Pts in the non-tBRCAm cohort (n~906) will be randomized (1:1:1) before cycle 2 to: a) chemo + bev + placebo (for 6 cycles) followed by bev (15 mg/kg [total 15 months]) + placebo maintenance treatment (IV and tablets); b) chemo + bev + durva (6 cycles) followed by bev + durva (1120 mg q3w [total 15 months]) + placebo (tablets) maintenance treatment; or c) chemo + bev + durva (6 cycles) followed by bev + durva + olap (300 mg bd tablets [24 months]) maintenance treatment. Pts in the open-label tBRCAm cohort (n~150) will receive 6 cycles of chemo + durva followed by durva + olap maintenance therapy, with optional use of bev. The primary endpoint of progression-free survival will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, overall response rate and duration of response. Enrollment began in January 2019. Clinical trial information: NCT03737643.


2017 ◽  
Vol 9 (9) ◽  
pp. 579-588 ◽  
Author(s):  
Davide Caruso ◽  
Anselmo Papa ◽  
Silverio Tomao ◽  
Patrizia Vici ◽  
Pierluigi Benedetti Panici ◽  
...  

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.


2017 ◽  
Vol 27 (6) ◽  
pp. 1141-1148 ◽  
Author(s):  
Gabriella Ferrandina ◽  
Giulia Amadio ◽  
Ida Paris ◽  
Mariagrazia Distefano ◽  
Eleonora Palluzzi ◽  
...  

BackgroundTrabectedin (T) plus pegylated liposomal doxorubicin (PLD) is approved for treatment of platinum-sensitive recurrent ovarian cancer (ROC). Despite the recommendations and guidelines, variations in managing T/PLD administration in routine clinical practice cannot be excluded. We aimed at setting up an Italian survey collecting data about management of T/PLD administration in ROC patients.MethodsWe carried out the development of a questionnaire-based survey on routine clinical practice in the management of ROC patients administered T/PLD. The survey registered the physicians’ approach to modification/discontinuation of treatment, type of modifications, reasons why, and so on. The survey was transmitted to medical oncologists and gynecologic oncologists practicing in national centers/institutions.ResultsFifty-eight Italian centers/institutions returned the compiled questionnaire; participants practiced at community cancer centers or hospitals (56.9%), academic institutions (36.2%), and other settings (private clinics, etc) (6.9%). There was no statistically significant difference in the distribution of practice setting according to geographic areas. Most responders were medical oncologists (84.5%) and were members (82.8%) of at least 1 scientific society or cooperative group. Almost 31.5% of responders reported interruption of the whole treatment, mostly because of toxicity (41.2%), followed by patients’ choice (29.4%), or achievement of clinical benefit (23.5%). Dose reduction was referred by 47.4% of responders. Reduction of dose for both drugs was referred by 88.5% of responders, and the extent of dose reduction ranged between 10% and 30%.ConclusionsThis survey highlights the gaps in transposing evidence-based or consensus guidelines in the real-world management of T/PLD administration; these findings could be useful in order to focus the attention on specific knowledge and/or experience gaps and plan pertinent educational programs.


Author(s):  
Hongyan Cheng ◽  
Junjun Yang ◽  
Huixin Liu ◽  
Yang Xiang

Abstract Purpose To investigate the efficacy and safety of poly (adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors (including their different types) as maintenance therapy in women with newly diagnosed ovarian cancer, and to explore whether this therapy produces a survival benefit in a subgroup population with specific clinical characteristics. Methods We searched MEDLINE, EMBASE, the Cochrane Library, Web of Science and relevant clinical research registry platforms on October 1, 2019, and included randomized controlled trials (RCTs) that compared PARP inhibitors with placebo in women (aged ≥ 18 years) with newly diagnosed epithelial ovarian cancer. Results We identified four RCTs with 3,070 participants. Compared with placebo, PARP inhibitor maintenance therapy showed a clinically significant benefit on progression free survival (PFS) in homologous recombination deficiency (HRD) positive population (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.29–0.53). In contrast, no clear differences were identified between the groups in the HRD negative population (HR, 0.83; 95% CI 0.67–1.03). Further, there was no clear difference between the groups in terms of other outcomes (overall survival, health-related quality of life, and adverse events). Conclusions PARP inhibitor maintenance therapy significantly prolongs the PFS of patients with newly diagnosed ovarian cancer, especially in HRD positive patients. The diagnostic test used to determine HRD status plays an important role in guiding PARP inhibitor maintenance therapy. Compared with placebo, the effect of PARP inhibitors on ovarian cancer was probably not affected by the International Federation of Gynecology and Obstetrics stage status, response to first-line chemotherapy, and residual macroscopic disease after debulking surgery.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6068-6068 ◽  
Author(s):  
Fabian Trillsch ◽  
Sven Mahner ◽  
Beyhan Ataseven ◽  
Rebecca Asher ◽  
Coraline Dubot ◽  
...  

6068 Background: Adding olaparib as maintenance treatment to BRCA-1/2 mutated patients (pts) with recurrent platinum-sensitive ovarian cancer (PSOC) has significantly improved progression-free survival (PFS) as well as patient-centered endpoints. As BRCA mutated pts tend to be younger, specific information on efficacy and safety of olaparib for elderly pts is of special interest. Methods: 295 pts from the SOLO2 trial that randomly assigned to olaparib or placebo were categorized according to age cutoff at 65 years. The efficacy and tolerability of olaparib relative to placebo within in each age group was assessed based on PFS and toxicity outcomes. Quality of life (QoL) was assessed using EQ-5D-5L descriptive system score and FACT Trial Outcome Index (TOI) and evaluated using generalized estimating equations (GEE) and time without significant symptoms of toxicity (TWiST) analysis. Results: Baseline characteristics were similar in pts ≥65 years (N=62; 21%) compared to pts <65 years (N=233; 79%), except for more BRCA2 mutations in elderly pts (39% vs. 23%). There was no significant difference in the magnitude of PFS benefit from olaparib in elderly as compared with younger pts (interaction P=0.33). The PFS adjusted hazard ratio (HR) of olaparib vs. placebo arms were respectively HR≥65 0.43 (95%-confidence interval [CI] 0.24-0.81) and HR<65 0.31 (95%-CI 0.22-0.43). Elderly and younger pts also had comparable safety profiles with no significant differences in median time on olaparib treatment (≥65: 27 vs. <65: 33 months), percentage of pts experiencing at least one grade >2 adverse event with olaparib (≥65: 73% vs. <65: 79%), or requiring at least one dose interruption or dose reduction (≥65: 77.5 vs. <65: 77.6%). No differences were found with regards to QoL scores. Quality adjusted TWiST analysis showed only non-significant differences in duration of good QoL under olaparib (≥65: 8.02 vs. <65: 9.24 months, P=0.48). Conclusions: In this large cohort of BRCA mutated PSOC pts treated with a PARP inhibitor within a phase III trial, no significant differences were detected in terms of efficacy, safety, and QoL with olaparib treatment for pts ≥65 years compared to younger pts. This information supports the use of PARP inhibitors as maintenance therapy for PSOC pts irrespective of age. Clinical trial information: NCT01874353.


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