scholarly journals Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for post-progression PARP inhibitor therapy

2015 ◽  
Vol 137 ◽  
pp. 8
Author(s):  
U.A. Matulonis ◽  
P. Harter ◽  
C. Gourley ◽  
M. Friedlander ◽  
I.B. Vergote ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Maintenance Therapy ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Serous Ovarian Cancer ◽  
Platinum Sensitive

Overall survival and updated progression-free survival results from a randomized phase 2 trial comparing the combination of olaparib and cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5535-5535 ◽  
Author(s):  
Joyce F. Liu ◽  
William Thomas Barry ◽  
Michael J. Birrer ◽  
Jung-min Lee ◽  
Ronald J. Buckanovich ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Free Survival ◽  
Angiogenic Therapy ◽  
Platinum Sensitive

5535 Background: We previously reported that the combination of cediranib (ced) and olaparib (olap) improved progression-free survival (PFS) and overall response rates (ORR) in women with recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related ovarian cancer (OvCa) (NCT 01116648). We conducted an updated PFS and overall survival (OS) analysis. Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. PFS was defined as time from randomization to radiographic progression or death. OS was defined as time from randomization to death. Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). As of Dec 21, 2016, 67 pts had a PFS event, and 52 pts had an OS event. Updated median PFS was 8.2 mos for Olap and 16.5 mos for Ced/Olap (HR 0.50, 95% CI 0.30-0.83, p=0.007). Median OS was 33.3 mos for Olap and 44.2 mos for Ced/Olap (HR 0.64, 95% CI 0.36-1.11, p=0.11). Within known germline BRCA mut carriers, updated PFS was 16.5 vs 16.4 mos (HR 0.75, p=0.42), and OS was 40.1 vs 44.2 mos (HR 0.79, p=0.55) for Olap and Ced/Olap, respectively. In pts without known germline BRCA mut, updated PFS was 5.7 vs 23.7 mos (HR 0.32, p=0.002), and OS was 23.0 vs 37.8 mos (HR 0.48, p=0.074). Conclusions: Updated PFS results consistently demonstrated that Ced/Olap significantly extended PFS compared to Olap in the overall population of women with plat-sens OvCa. In this Phase 2 study not powered to detect OS diferences, there was a trend towards OS improvement with Ced/Olap, particularly in pts without a known germline BRCA mutation. Results from ongoing studies of this oral combination in OvCa are of clinical interest. Clinical trial information: NCT 01116648.

scholarly journals Gynecologic Cancers: Emerging Novel Strategies for Targeting DNA Repair Deficiency

2016 ◽  
pp. e259-e268 ◽  
Author(s):  
Rebecca S. Kristeleit ◽  
Rowan E. Miller ◽  
Elise C. Kohn
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Inhibitor Therapy ◽  
Molecular Therapy ◽  
Parp Inhibition ◽  
Gynecologic Cancers ◽  
Brca Mutations ◽  
Individual Gene

The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a subset of women without BRCA mutations were shown to respond to these drugs (termed “ BRCAness”). It was hypothesized that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined. They include individual gene defects (e.g., RAD51 mutation, CHEK2 mutation), homozygous somatic loss, and whole genome properties such as genomic scarring. Testing this knowledge is possible when selecting patients to receive molecular therapy targeting DNA repair, not only for patients with ovarian cancer but also endometrial and cervical cancers. The validity of HRD assays and multiple gene sequencing panels to select a broader population of patients for treatment with PARP inhibitor therapy is under evaluation. Other non-HRD targets for exploiting DNA repair defects in gynecologic cancers include mismatch repair (MMR), checkpoint signaling, and nonhomologous end-joining (NHEJ) DNA repair. This article describes recent evidence supporting strategies in addition to BRCA mutation for selecting patients for treatment with PARP inhibitor therapy. Additionally, the challenges and opportunities of exploiting DNA repair pathways other than homologous recombination for molecular therapy in gynecologic cancers is discussed.

PARP inhibitor maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer: A cost-effectiveness analysis

2015 ◽  
Vol 139 (1) ◽  
pp. 59-62 ◽  
Author(s):  
Haller J. Smith ◽  
Christen L. Walters Haygood ◽  
Rebecca C. Arend ◽  
Charles A. Leath ◽  
J. Michael Straughn
Keyword(s):  
Ovarian Cancer ◽  
Cost Effectiveness ◽  
Maintenance Therapy ◽  
Parp Inhibitor ◽  
Recurrent Ovarian Cancer ◽  
Cost Effectiveness Analysis ◽  
Platinum Sensitive ◽  
Effectiveness Analysis

DUO-O: A randomized phase III trial of durvalumab (durva) in combination with chemotherapy and bevacizumab (bev), followed by maintenance durva, bev and olaparib (olap), in newly diagnosed advanced ovarian cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5598-TPS5598 ◽  
Author(s):  
Philipp Harter ◽  
Mariusz Bidziński ◽  
Nicoletta Colombo ◽  
Anne Floquet ◽  
Maria Jesús Rubio Pérez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Maintenance Treatment ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Phase Iii ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
First Line Treatment

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.

Real-world treatment patterns of maintenance therapy in platinum-sensitive recurrent epithelial ovarian cancer: Are some patients missing out?

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e18042-e18042
Author(s):  
Haley Moss ◽  
Angeles Alvarez Secord ◽  
Jessica Perhanidis ◽  
Carol Hawkes
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Active Surveillance ◽  
Real World ◽  
Brca Mutation ◽  
Treatment Patterns ◽  
World Population ◽  
Brca Mutations ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy

e18042 Background: The clinical utility of maintenance therapy (MT) for patients with platinum-sensitive recurrent ovarian cancer (PSROC) has been validated in several clinical trials. We assessed real world treatment patterns using a US nationwide electronic health record database. Methods: A retrospective study of patients with PSROC between March 2017 and July 2019 was conducted using the Flatiron Health database. This longitudinal, demographically and geographically diverse de-identified database covers > 2.2 million oncology patients in > 280 cancer clinics. Patients were excluded if second or third line (2L or 3L) platinum-based chemotherapy (PBT) regimens included less than four or more than eight cycles of platinum. Information regarding somatic or germline BRCA mutations and homologous recombination deficiency (HRD) were obtained. Results: 2292 patients with PSROC were identified (had 2L or 3L treatment); 1214 of these received PBT at recurrence; 610 completed the PBT for recurrence on or after March 2017; 351 received 4–8 cycles of PBT; 225 patients had ≥2 months of active surveillance or were receiving MT of PARPi or bevacizumab (B) and were included in this analysis. 183 patients (80%) had BRCA testing and 14 patients (6%) had HRD testing. 46 (20%) had a germline or somatic BRCA mutations (t BRCA), 134 (59%) had a wildtype wt BRCA gene, and 48 (21%) were unknown. Of patients with tBRCA, 63% received a PARP inhibitor (PARPi), 17% received B, 20% received active surveillance. Of patients with wt BRCA, 40% received a PARPi, 24% received B, and 37% received active surveillance. Olaparib was the most commonly used PARPi among tBRCA patients (26%), while niraparib was most commonly used among wt BRCA patients (21%). MT was more common in younger patients, those with a better performance status and with a BRCA mutation. MT use trend increased by 21% during the study period. As PARPi use increased, the use of active surveillance as a post-platinum regimen decreased during the later time periods (Table). Conclusions: In this real world population, the majority of patients with PSROC are receiving maintenance therapy. While genetic testing is improving, universal testing of all patients with ovarian cancer remains the goal. The results provide insight into the shifting treatment patterns for patients with ovarian cancer. [Table: see text]

Concordance between CA-125 and RECIST progression (PD) in patients with germline BRCA-mutated platinum-sensitive, relapsed ovarian cancer treated with a PARP inhibitor (PARPi) as maintenance therapy after response to chemotherapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6014-6014 ◽  
Author(s):  
Angelina Tjokrowidjaja ◽  
Chee Khoon Lee ◽  
Michael Friedlander ◽  
Val Gebski ◽  
Laurence Gladieff ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Positive Predictive Value ◽  
Maintenance Therapy ◽  
Predictive Value ◽  
Parp Inhibitor ◽  
Ca 125 ◽  
Normal Range ◽  
Primary Analysis ◽  
Platinum Sensitive ◽  
Response To Chemotherapy

6014 Background: There are no data to support CA-125 as a surrogate biomarker for ovarian cancer PD in patients on maintenance therapy with a PARPi. We aimed to assess the concordance of PD by CA-125 with RECIST PD in patients treated with maintenance PARPi. Methods: We extracted data on PD as defined by GCIG CA-125 and investigator-assessed RECIST from the SOLO2/ENGOT-Ov21 (NCT01874353) trial. Patients were categorized into: (i) CA-125 and RECIST non-PD concordant; (ii) CA-125 and RECIST PD concordant; and (iii) CA-125 and RECIST discordant. We excluded those with PD other than by RECIST, PD on date of randomization, and no repeat CA-125 beyond baseline. To assess the concordance of CA-125 PD with RECIST PD and CA-125 non-PD with RECIST non-PD, we computed the positive predictive value (PPV), i.e. the probability that patients with CA-125 PD also had RECIST PD, and negative predictive value (NPV), i.e. probability that patients with no CA-125 PD also did not have RECIST PD, respectively. Results: Of 295 randomised patients, 275 (184 olaparib, 91 placebo) were included in the primary analysis. 80 (29%) had CA-125 PD and 77 had concordant RECIST PD, resulting in a PPV of 96% (95% CI 90%-99%). Of 195 patients without CA-125 PD, 101 also did not have RECIST PD, resulting in a NPV of 52% (95% CI 45%-59%; Table). Among those with RECIST PD (n = 171), a greater proportion of patients with RECIST-only PD had a normal baseline CA-125 than those with both CA-125 and RECIST PD (94% vs 69%; p< 0.001). Of 94 patients without CA-125 PD but had RECIST PD, 65 (69%) had CA-125 that remained within normal range, while 27 (29%) had rising and elevated CA-125 that did not meet the criteria for GCIG CA125-PD. Discordance between RECIST PD and CA-125 non-PD was similar in early (≤12 weeks) and late ( > 12 weeks) PD (56% vs 55%, respectively; p= 0.96). Conclusions: Almost half the patients with RECIST PD did not have CA-125 PD and most had CA-125 still within the normal range. Regular imaging should be considered as part of surveillance in patients on maintenance olaparib rather than relying on CA-125 alone. [Table: see text]

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