Maintenance olaparib plus bevacizumab (bev) after platinum-based chemotherapy plus bev in patients (pts) with newly diagnosed advanced high-grade ovarian cancer (HGOC): Efficacy by BRCA1 or BRCA2 mutation in the phase III PAOLA-1 trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6039-6039
Author(s):  
Domenica Lorusso ◽  
Jean-Pierre Lotz ◽  
Philipp Harter ◽  
Claire Cropet ◽  
Maria Jesus Rubio Pérez ◽  
...  
Keyword(s):  
Brca Mutation ◽  
Brca1 Mutation ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Phase Iii ◽  
Primary Data ◽  
High Grade ◽  
Newly Diagnosed ◽  
First Line ◽  
Platinum Based Chemotherapy

6039 Background: In PAOLA-1/ENGOT-ov25 (NCT02477644), adding the PARP inhibitor olaparib to maintenance bev after first-line platinum-based chemotherapy plus bev led to a statistically significant progression-free survival (PFS) benefit in pts with advanced HGOC (HR 0.59; 95% CI 0.49–0.72) (Ray-Coquard et al. 2019). Retrospective subgroup analysis in GOG-0218 (Norquist et al. 2018) suggested BRCA mutation (BRCAm) status did not significantly impact the PFS benefit provided by bev. We explored the efficacy of olaparib plus bev by BRCA1 mutation ( BRCA1m) or BRCA2 mutation ( BRCA2m) in PAOLA-1. Methods: PAOLA-1 is a randomized, double-blind, Phase III trial in pts with newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid OC, fallopian tube or primary peritoneal cancer receiving platinum-based chemotherapy plus bev then maintenance bev. Pts unrestricted by surgical outcome or BRCAm status and in response to first-line therapy were randomized to maintenance olaparib tablets (300 mg bid for up to 24 months) plus bev (15 mg/kg q3w for up to 15 months in total) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. Investigator-assessed PFS (modified RECIST v1.1) by BRCAm was a predefined analysis. Results: Of 806 randomized pts, 160 (20%) had tumor BRCA1m, 76 (9%) had tumor BRCA2m and 1 (<1%) had both. Median PFS follow-up was 24.1 and 27.4 months in BRCA1m and BRCA2m pts, respectively. At primary data cutoff, PFS was prolonged with olaparib plus bev versus placebo plus bev in BRCA1m pts and BRCA2m pts (Table). The percentage of BRCA1m pts who received olaparib plus bev and were progression-free at 1 and 2 years was 95% and 73% (vs. 70% and 29% for placebo plus bev) and for BRCA2m pts was 89% and 84% (vs. 84% and 53%) (Kaplan-Meier estimates). Conclusions: In PAOLA-1, maintenance olaparib plus bev provided a significant PFS benefit versus placebo plus bev in all pts analysed, regardless of whether they had BRCA1m or BRCA2m. The median PFS in the control arm suggests a role for bev in this subgroup and the hazard ratio versus an active control arm shows the value of adding maintenance olaparib to bev. Clinical trial information: NCT02477644. [Table: see text]

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.

Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients (pts) by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5551-5551
Author(s):  
Michael Friedlander ◽  
Kathleen N. Moore ◽  
Nicoletta Colombo ◽  
Giovanni Scambia ◽  
Byoung-Gie Kim ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Statistical Tests ◽  
Brca2 Mutation ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Primary Data ◽  
Newly Diagnosed ◽  
Brca1 And Brca2 ◽  
Platinum Based Chemotherapy

5551 Background: In SOLO1 (NCT01844986), maintenance olaparib resulted in a significant improvement in progression-free survival (PFS) for newly diagnosed, BRCA1- and/or BRCA2-mutated, advanced ovarian cancer pts compared with placebo (HR 0.30, 95% CI 0.23–0.41; median not reached vs 13.8 months; Moore et al. N Engl J Med 2018). We investigated PFS in SOLO1 for the subgroups of pts with BRCA1 mutations ( BRCA1m) or BRCA2 mutations ( BRCA2m). Methods: All pts were in clinical complete or partial response to platinum-based chemotherapy and were randomized to maintenance olaparib (300 mg twice daily; tablets) or placebo. After 2 years, pts with no evidence of disease discontinued study treatment, but pts with evidence of disease could continue study treatment. PFS by BRCAm was a predefined analysis. BRCAm were identified by central germline (Myriad or BGI) or local testing; Foundation Medicine testing confirmed tumor BRCAm. Results: Median follow-up for PFS was ~41 months in the olaparib and placebo arms. Of 391 randomized pts, 282 had BRCA1m (72%), 106 had BRCA2m (27%) and three (1%) had both (Table). Two pts in the olaparib arm had somatic BRCAm (one BRCA1m, one BRCA2m); all others had germline BRCAm. At the primary data cut-off, 155 pts in the BRCA1-mutated group (55%), 43 in the BRCA2-mutated group (41%) and none in the BRCA1/2 -mutated group had disease progression. The percentage of BRCA1-mutated pts who received olaparib and were progression-free at 1, 2 and 3 years was 86%, 69% and 53% (vs 52%, 36% and 26% receiving placebo) and for BRCA2-mutated pts was 92%, 85% and 80% (vs 50%, 32% and 29%, respectively). Conclusions: Significant PFS benefit with olaparib versus placebo was demonstrated for all pts, regardless of whether they had BRCA1m or BRCA2m. Statistical tests were not used to compare BRCA1- and BRCA2-mutated pts, but those with BRCA2m appeared to receive greater benefit from maintenance olaparib than those with BRCA1m. Clinical trial information: NCT01844986. [Table: see text]

Clinical outcomes in pancreatic adenocarcinoma (PAC) associated with a known BRCA mutation.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 268-268 ◽  
Author(s):  
M. A. Lowery ◽  
Z. K. Stadler ◽  
E. Ludwig ◽  
E. Salo-Mullen ◽  
D. R. D'Adamo ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Germ Line ◽  
Advanced Disease ◽  
Brca Mutation ◽  
Brca1 Mutation ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Genetic Mutation ◽  
Platinum Based Chemotherapy ◽  
Increased Risk

268 Background: BRCA1 and -2 germ-line mutations are associated with increased risk of PAC; approximately 5% of all cases of PAC are estimated to be due to an inherited genetic mutation (Lynch, HT, et al. Pancreatology, 2001;1(5):466-471). Other BRCA-associated cancers have demonstrated increased sensitivity to platinum chemotherapy and PARP inhibitors (PARPi) with improved clinical outcomes compared to sporadic cases (J Clin Oncol, 2008 Dec 1;26(34):5530-6). Outcomes in BRCA-associated pancreatic cancer are unknown. Methods: Patients with a known BRCA1 or -2 mutation and a diagnosis of PAC were retrospectively identified from the MSKCC Familial Pancreas Cancer Registry and via institutional database review. Outcomes and clinical characteristics were reviewed. 7 patients (1 male) with BRCA2 mutation and PAC, 4 patients (1 male) with BRCA1 mutation and PAC, were identified. Two further cases of BRCA mutation and cholangiocarcinoma were identified. Results: See Table for patient demographics. Treatment for advanced disease included a PARP inhibitor (PARPi) in 2 cases; both pts had a radiologic partial response (PR) to therapy. Five patients received platinum-based chemotherapy for advanced disease, 4 of whom had a PR. Median survival for all patients was 27.6 months. Conclusions: The use of platinum- containing chemotherapy, radiation therapy, and PARPi to target the BRCA-associated defective DNA repair mechanism is deserving of further investigation in these patients. PARPi have demonstrated promising efficacy in patients with BRCA-mutated breast and ovarian cancer and are undergoing prospective evaluation in PAC. Genetic testing in patients presenting with a personal history or strong family history of BRCA associated cancers may help to guide choice of therapy. [Table: see text] No significant financial relationships to disclose.

Olaparib maintenance therapy in patients (pts) with a BRCA1 and/or BRCA2 mutation (BRCAm) and newly diagnosed advanced ovarian cancer (OC): SOLO1 China cohort.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5554-5554
Author(s):  
Lingying Wu ◽  
Jianqing Zhu ◽  
Rutie Yin ◽  
Xiaohua Wu ◽  
Ge Lou ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Advanced Ovarian Cancer ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Platinum Based Chemotherapy ◽  
Grade 3

5554 Background: SOLO1 (NCT01844986) is a randomized, double-blind, Phase III trial evaluating the efficacy and safety of the PARP inhibitor, olaparib, as maintenance monotherapy in newly diagnosed advanced OC pts with a BRCAm. A separate pt cohort evaluated the efficacy and safety of olaparib in Chinese pts in this setting. Methods: The China cohort of SOLO1 planned to enroll ~53 newly diagnosed OC pts who had completed first-line platinum-based chemotherapy and were in clinical complete or partial response. This sample size provided around a 90% chance to observe an HR < 1, assuming a true HR = 0.62. Pts were randomized 2:1 to olaparib (300 mg bid; tablet) vs placebo. The primary endpoint was investigator-assessed progression-free survival (PFS; modified RECIST v1.1). Sensitivity analysis of PFS was performed by blinded independent central review (BICR). Results: All 64 randomized pts received study treatment (olaparib, n = 44; placebo n = 20). Median follow-up was ~30 months in both arms. Median PFS was not reached in the olaparib arm and was 9.3 months in the placebo arm (Table). The most common AEs in the olaparib group were nausea (n = 28, 63.6%), anemia (n = 25, 56.8%) and vomiting (n = 18, 40.9%). Grade ≥3 AEs occurred in 56.8% of olaparib pts vs 30.0% of placebo pts; the most common grade ≥3 AE was anemia (n = 16, 36.4%). Olaparib dose interruptions, reductions and discontinuations occurred in 56.8%, 27.3% and 6.8% of pts, respectively (vs in 30.0%, 10% and 0% of pts in the placebo arm). Conclusions: In the China cohort of SOLO1, a clinically relevant improvement in investigator-assessed PFS was observed in newly diagnosed OC pts receiving olaparib maintenance therapy. Olaparib treatment led to a 54% reduction in risk of progression or death vs placebo. The safety results were consistent with the known profile of olaparib in Chinese pts. Clinical trial information: NCT01844986. [Table: see text]

Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial.

2019 ◽  
Vol 37 (18_suppl) ◽  
pp. LBA4-LBA4 ◽  
Author(s):  
Hedy L. Kindler ◽  
Pascal Hammel ◽  
Michele Reni ◽  
Eric Van Cutsem ◽  
Teresa Macarulla Mercade ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Maintenance Treatment ◽  
Controlled Trial ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Phase Iii ◽  
First Line ◽  
Meaningful Improvement ◽  
Phase Iii Trial ◽  
Platinum Based Chemotherapy

LBA4 Background: Pancreatic cancer (PC) pts with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) have shown response to the PARP inhibitor olaparib (Kaufman 2015). POLO is the first phase III trial to evaluate efficacy of maintenance treatment with a PARP inhibitor in PC. Methods: POLO is an international, randomized, double-blind, placebo-controlled trial of pts with a gBRCAm and pancreatic adenocarcinoma who had received ≥16 weeks of first-line PBC for metastatic disease without progression. Pts were randomized 3:2 to maintenance olaparib (O) tablets (300 mg bid) or placebo (P). Treatment began 4–8 weeks after last PBC dose, continuing until investigator-assessed progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by blinded independent central review (modified RECIST 1.1). Results: We screened 3315 pts, identified 247 with a gBRCAm, randomized 154 (O 92, P 62), and treated 151 (O 90, P 61). Pt characteristics (O/P): age, median (range) 57 (37–84)/57 (36–75); male, 58%/50%; ECOG performance status 0, 71%/61%. With 104 events, PFS was significantly improved with O vs. P (hazard ratio [HR] 0.53; 95% CI 0.35, 0.82; p = 0.0038; median PFS was 7.4 vs. 3.8 months [mo], respectively) and consistent irrespective of response to prior PBC (complete/partial HR 0.62; stable disease HR 0.50). From 6 mo, the % of pts progression-free in the O arm was more than twice that in the P arm (Table). At the interim overall survival analysis (46% maturity), HR was 0.91 (95% CI 0.56, 1.46; p = 0.68). Grade ≥3 adverse events (AE) occurred in 40% of O- and 23% of P-treated pts; 5.5% and 1.7% of pts, respectively, discontinued treatment due to an AE. Conclusions: Maintenance olaparib provided a statistically significant and clinically meaningful improvement in PFS in mPC pts with a gBRCAm who had not progressed on PBC. Safety was consistent with the known profile for olaparib. POLO is the first phase III trial to validate a biomarker-driven treatment in PC. Clinical trial information: NCT02184195. [Table: see text]

Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6002-6002 ◽  
Author(s):  
Andres Poveda ◽  
Anne Floquet ◽  
Jonathan A. Ledermann ◽  
Rebecca Asher ◽  
Richard T. Penson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Phase Iii ◽  
Tolerability Profile ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
Long Term Treatment

6002 Background: SOLO2 (ENGOT ov-21; NCT01874353) showed that maintenance therapy with the PARP inhibitor olaparib in pts with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation (BRCAm) led to a statistically significant improvement in median progression-free survival (PFS) of 13.6 months vs placebo (hazard ratio [HR] 0.30). Time to second progression or death significantly improved (Pujade-Lauraine et al Lancet Oncol 2017) and a quality-adjusted PFS benefit was seen (Friedlander et al Lancet Oncol 2018) with maintenance olaparib vs placebo. We report the preplanned final OS analysis for SOLO2. Methods: Pts with PSROC and a BRCAm who had received ≥2 lines of treatment and were in response to their most recent platinum-based chemotherapy received maintenance olaparib (300 mg bid tablets) or placebo. Pts were stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (>6–12 months vs >12 months). OS was a secondary endpoint. The only preplanned OS sensitivity analysis was an OS analysis in the Myriad germline BRCAm subset (Myriad BRAC Analysis test). Results: At final data cut-off (Feb 3, 2020), median follow-up was 65 months in both treatment arms. A long-term treatment benefit was seen with olaparib vs placebo with an OS HR of 0.74 (95% confidence interval [CI] 0.54–1.00) in the full analysis set (FAS; unadjusted for crossover; 38.4% of placebo pts crossed over to a PARP inhibitor) (Table). At 5 years: by Kaplan-Meier estimates, 28.3% of pts in the olaparib arm vs 12.8% of pts in the placebo arm were alive and had still not received subsequent treatment; 42.1% of olaparib pts vs 33.2% of placebo pts were alive. The long-term tolerability profile of olaparib was generally consistent with that reported previously. Conclusions: In the final analysis of SOLO2, maintenance olaparib provided an unprecedented improvement of 12.9 months in median OS vs placebo. This is the first study with olaparib tablets, and the first since Study 19 (NCT00753545), to provide long-term follow-up and final OS data in pts with PSROC and a BRCAm. Clinical trial information: NCT01874353. [Table: see text]

Maintenance olaparib after platinum-based chemotherapy in patients (pts) with newly diagnosed advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): Efficacy by surgical and tumor status in the Phase III SOLO1 trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5541-5541 ◽  
Author(s):  
Cara Amanda Mathews ◽  
Kathleen N. Moore ◽  
Nicoletta Colombo ◽  
Giovanni Scambia ◽  
Byoung-Gie Kim ◽  
...  
Keyword(s):  
Residual Disease ◽  
Brca Mutation ◽  
Objective Response ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Timing Of Surgery ◽  
Phase Iii ◽  
Case Report Form ◽  
Newly Diagnosed ◽  
Platinum Based Chemotherapy

5541 Background: In SOLO1 (NCT01844986), maintenance olaparib significantly improved progression-free survival (PFS) vs placebo (HR 0.30; 95% CI 0.23–0.41; Moore et al. N Engl J Med 2018) in pts with newly diagnosed advanced OC and a BRCAm. This analysis evaluates olaparib efficacy by timing of surgery, presence of residual tumor following surgery and response status after completion of chemotherapy in SOLO1. Methods: Pts underwent cytoreductive surgery and were in clinical complete response (CR) or partial response (PR) after platinum-based chemotherapy. Pts were stratified by response and received olaparib tablets 300 mg twice daily or placebo. Investigator-assessed PFS and objective response were assessed using modified RECIST v1.1. Results: 260 pts were randomized to olaparib and 131 to placebo; one pt did not receive placebo. Median follow-up was 41 months in both arms. 63% and 35% of pts underwent upfront and interval surgery, 21% and 76% had residual and no residual macroscopic disease after surgery, and 74% and 26% entered the study in clinical CR and PR (based on electronic case report form [eCRF] data). PFS was significantly improved regardless of the timing of surgery, residual disease status after surgery or response after platinum-based chemotherapy (Table). In pts with baseline radiologic evidence of disease (n=80; eCRF), the objective response rate was 43% for olaparib (CR, 28%) and 23% for placebo (CR, 12%). Conclusions: Maintenance olaparib improved outcomes compared with placebo in pts with newly diagnosed advanced OC and a BRCAm, regardless of surgical or tumor status. Clinical trial information: NCT01844986. [Table: see text]

A phase III study comparing single-agent olaparib or the combination of cediranib and olaparib to standard platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6003-6003 ◽  
Author(s):  
Joyce F. Liu ◽  
Mark F. Brady ◽  
Ursula A. Matulonis ◽  
Austin Miller ◽  
Elise C. Kohn ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Primary Endpoint ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Phase Iii ◽  
High Grade ◽  
Primary Analysis ◽  
Open Label ◽  
Platinum Based Chemotherapy

6003 Background: Combination cediranib (C) and olaparib (O) improved progression-free survival (PFS) in patients (pts) with relapsed platinum (plat)-sensitive high-grade ovarian cancer (ovca) compared to O alone in a Phase 2 trial (NCT01116648). We conducted this randomized, open-label Phase 3 trial (NCT02446600) to assess whether combination C+O, or O alone, was superior to standard of care (SOC) plat-based therapy in relapsed plat-sensitive ovca. Methods: Eligible pts had recurrent plat-sensitive [ > 6-month plat-free interval (PFI)] high-grade serous or endometrioid, or BRCA-related, ovca. One prior non-plat therapy and unlimited prior plat-therapies were allowed; prior anti-angiogenics in the recurrent setting or prior PARP inhibitor were exclusions. Pts were randomized 1:1:1 to SOC (carboplatin/paclitaxel; carboplatin/gemcitabine; or carboplatin/liposomal doxorubicin), O (300mg twice daily), or C+O (C 30mg daily + O 200mg twice daily). Randomization was stratified by g BRCA status, PFI (6-12 vs > 12 months), and prior anti-angiogenic therapy. Target sample size was 549 pts; primary analysis occurred 2 years after the last pt enrolled. The primary endpoint was PFS. Type 1 error = 0.025 was controlled by a gatekeeping hierarchy that assessed C+O vs SOC, then O alone vs SOC, and finally C+O vs O. All maintenance therapy was prohibited. Results: Between 4FEB2016 and 13NOV2017, 565 pts enrolled (187 SOC, 189 O, 189 C+O), and 528 pts initiated treatment (166 SOC, 183 O, 179 C+O). 23.7% of patients had g BRCAmut. Median follow-up was 29.1 months. 53 pts on SOC initiated non-protocol therapy (predominantly PARP inhibitor maintenance) before disease progression. The hazard ratio (HR) for PFS was 0.856 (95% CI 0.66-1.11, p = 0.08, 1-tail) between C+O and SOC and 1.20 (95% CI 0.93-1.54) between O and SOC, with median PFS of 10.3, 8.2, and 10.4 months for SOC, O, and C+O, respectively. Response rates were 71.3% (SOC), 52.4% (O), and 69.4% (C+O). In gBRCA pts, HR for PFS was 0.55 (95% CI 0.73-1.30) for C+O vs SOC, and 0.63 (95% CI 0.37-1.07) for O vs SOC. In non-g BRCA pts, HR for these comparisons was 0.97 (95% CI 0.73-1.30) and 1.41 (1.07-1.86). No OS differences between arms were observed at 44% events. Pts receiving C+O (vs SOC) had more frequent Grade 3 or higher gastrointestinal (30.1% vs 8.4%), hypertension (31.7% vs 1.8%), and fatigue events (17.5% vs 1.8%). Conclusion: C+O demonstrated similar activity to SOC in relapsed plat-sensitive ovca but did not meet the primary endpoint of improved PFS. Clinical trial information: NCT02446600.

scholarly journals The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer

2020 ◽  
Vol 9 (7) ◽  
pp. 2239
Author(s):  
Ludivine Dion ◽  
Isis Carton ◽  
Sylvie Jaillard ◽  
Krystel Nyangoh Timoh ◽  
Sébastien Henno ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Genetic Alterations ◽  
High Grade ◽  
Dna Breaks ◽  
Brca Mutations ◽  
Platinum Based Chemotherapy

Epithelial ovarian cancer (EOC) affects 43,000 women worldwide every year and has a five-year survival rate of 30%. Mainstay treatment is extensive surgery and chemotherapy. Outcomes could be improved by molecular profiling. We conducted a review of the literature to identify relevant publications on molecular and genetic alterations in EOC. Approximately 15% of all EOCs are due to BRCA1 or BRCA2 mutations. Four histologic subtypes characterized by different mutations have been described: serous, endometrioid, mucinous, and clear-cell. Between 20–30% of high-grade serous EOCs have a BRCA mutation. Tumors with BRCA mutations are unable to repair double-strand DNA breaks, making them more sensitive to platinum-based chemotherapy and to PolyAdenosine Diphosphate-Ribose Polymerase (PARP) inhibitors. Olaparib is a PARP inhibitor with proven efficacy in BRCA-mutated ovarian cancer, but its effectiveness remains to be demonstrated in tumors with a BRCAness (breast cancer) profile (i.e., also including sporadic tumors in patients with deficient DNA repair genes). A universally accepted molecular definition of BRCAness is required to identify optimal theranostic strategies involving PARP inhibitors. Gene expression analyses have led to the identification of four subgroups of high-grade serous EOC: mesenchymal, proliferative, differentiated, and immunoreactive. These subtypes are not mutually exclusive but are correlated with prognosis. They are not yet used in routine clinical practice. A greater understanding of EOC subtypes could improve patient management.

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