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 timing of surgery and residual tumor status in the Phase III PAOLA-1 trial

2020 ◽  
Vol 159 ◽  
pp. 19
Author(s):  
C. Grimm ◽  
C. Cropet ◽  
I. Ray-Coquard
Keyword(s):  
Ovarian Cancer ◽  
Residual Tumor ◽  
Timing Of Surgery ◽  
Phase Iii ◽  
High Grade ◽  
Newly Diagnosed ◽  
Platinum Based Chemotherapy

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]

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]

PFS by blinded independent central review (BICR) in the VELIA trial of veliparib (V) plus carboplatin/paclitaxel (CP) and as monotherapy in newly diagnosed patients (pts) with high-grade serous ovarian cancer (HGSC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6077-6077
Author(s):  
Carol Aghajanian ◽  
Michael A. Bookman ◽  
Gini F. Fleming ◽  
Mark F. Brady ◽  
Elizabeth M. Swisher ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Safety Data ◽  
Phase Iii ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Newly Diagnosed ◽  
Primary Analysis ◽  
Population Analyses ◽  
Clinical Trial Information

6077 Background: The phase III VELIA trial (NCT02470585) demonstrated statistically significant improvement in PFS per investigator (INV) for V added to CP and continued as maintenance (CPV-V) vs. CP alone in pts with newly diagnosed HGSC in the BRCA mutated ( BRCAm), homologous recombination deficient (HRD), and whole populations. Here we present pre-specified analyses of PFS per BICR. Methods: Pts with Stage III-IV HGSC received V or Placebo (PL) with CP (6 cycles) and as maintenance (30 additional cycles). Primary analysis of PFS by INV compared CPV-V to CP alone in the BRCAm, HRD, and whole populations. Exploratory analyses of PFS in BRCA wildtype (wt) and non-HRD HGSC were performed. Radiologic tumor assessments were also prospectively submitted to an independent central reviewer for blinded assessment per RECIST v 1.1. PFS per BICR and rates of concordance between INV and BICR for determination of disease progression were analyzed. Safety data from the primary analysis were previously reported. Results: 1140 total pts were enrolled (CPV-V 382; CP 375). In the whole population, 26% of HGSCs were BRCAm and 55% were HRD. Concordance rates between INV and BICR were 68-85% by arm for each population. Analyses of PFS per BICR and per INV were consistent (Table). PFS was prolonged in the CPV-V vs. CP arm in all primary and exploratory populations assessed. Conclusions: Analyses of PFS per BICR supported the primary analysis of PFS per INV in the BRCAm, HRD, and whole populations, as well as exploratory BRCAwt and non-HRD populations. Median PFS per BICR was longer compared to PFS per INV assessments in all populations and in both arms. These findings support the reliability of PFS by INV in ovarian cancer trials. Alternate strategies like audits may be appropriate to support PFS by INV with less time and expense than full BICR. Clinical trial information: NCT02470585. [Table: see text]

NOGGO Ov-42/MAMOC: Rucaparib maintenance after bevacizumab maintenance following carboplatin-based first line-chemotherapy in ovarian cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6102-TPS6102
Author(s):  
Elena Ioana Braicu ◽  
Pauline Wimberger ◽  
Rolf Richter ◽  
Maren Keller ◽  
Petra Krabisch ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Residual Tumor ◽  
Phase Iii ◽  
High Grade ◽  
First Line ◽  
Tumor Mass ◽  
Antiangiogenic Drugs ◽  
Line Chemotherapy ◽  
Residual Tumor Mass

TPS6102 Background: Ovarian cancer (OC) is associated with the highest mortality rates among gynecological malignancies, with most patients being diagnosed in advanced stages. The most common histological subtype is high grade serous OC, which is characterized by deficiency in homologous recombination. Debulking surgery, followed by platinum based chemotherapy and bevacizumab (bev), followed by maintenance therapy with bev, is the standard therapy for advanced BRCA wild type (BRCAwt) OC patients in Germany. BRCA mutant patients will receive maintenance with olaparib, according to SOLO1 data. The anticancer effects of PARP inhibitors (PARPi) seem to be increased by the addition of antiangiogenic drugs. Preclinical data showed increased HRD in tumors pretreated with bev, and clinical trials showed a benefit of the combination of antiangiogenic drugs and PARPi vs. PARPi alone. NOGGO Ov-42/MAMOC trial (NCT04227522) is a phase III, randomized, placebo-controlled study evaluating rucaparib maintenance following bevacizumab maintenance for the treatment of advanced primary high grade BRCAwt OC. Methods: 190 patients with histologically confirmed advanced (FIGO stage IIIA- IV of the 2014 FIGO classification) high grade serous or high grade endometrioid (based on local histopathological findings) OC, fallopian tube cancer, primary peritoneal cancer or clear cell carcinoma of the ovary will be randomized 2:1 to receive either rucaparib 600mg BID or placebo as maintenance therapy following first line chemotherapy with 6 cycles of Carboplatin/Paclitaxel and at least 12 cycles of bev, given together with chemotherapy and as maintenance. Only BRCAwt patients will be included in the trial. Randomization is stratified by surgery planned timepoint (neoadjuvant vs. adjuvant), surgical outcome (no residual tumor mass vs. residual tumor mass), response to chemotherapy followed by bev (CR/NED vs. PR/SD) and study center. Treatment will continue for 24 months or until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint is PFS in BRCAwt patients per RECIST v1.1. Secondary endpoints are PFS2, quality of life (EORTC QLQ-C30/OV28, FSI, SF-12, PROC-CTCAE, every day memory questionnaire), daily activity, time to next medical intervention, time to next subsequent therapy, safety assessments and OS. Clinical trial information: NCT04227522.

Progression-free survival (PFS) and second PFS (PFS2) by disease stage in patients (pts) with homologous recombination deficiency (HRD)-positive newly diagnosed advanced ovarian cancer receiving bevacizumab (bev) with olaparib/placebo maintenance in the phase III PAOLA-1/ENGOT-ov25 trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5514-5514
Author(s):  
Patricia Pautier ◽  
Philipp Harter ◽  
Carmela Pisano ◽  
Claire Cropet ◽  
Susana Hernando Polo ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Residual Disease ◽  
Stage Iv ◽  
Figo Stage ◽  
Phase Iii ◽  
Stage Iii ◽  
Disease Stage ◽  
Newly Diagnosed ◽  
Platinum Based Chemotherapy ◽  
Interval Surgery

5514 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), the addition of maintenance olaparib to bev in pts with newly diagnosed advanced high-grade ovarian cancer (HGOC) resulted in a significant PFS benefit, particularly in HRD-positive (HRD+) pts (hazard ratio [HR] 0.33; 95% CI 0.25–0.45) (Ray-Coquard et al. NEJM 2019). We explored efficacy in HRD+ pts by disease stage. Methods: Pts with newly diagnosed, FIGO stage III–IV HGOC in response after platinum-based chemotherapy + bev received bev (15 mg/kg q3w for 15 months [mo]) + either olaparib (300 mg bid for 24 mo) or placebo (pbo). This exploratory analysis evaluated PFS (data cut-off [DCO]: Mar 22 2019) and PFS2 (DCO: Mar 22 2020) in HRD+ pts (tumor BRCA1/ BRCA2 mutation [tBRCAm] or genomic instability score [Myriad myChoice HRD Plus] ≥42) by FIGO stage. Results: 387/806 randomized pts (48%) were HRD+; 272/387 (70%) had stage III disease and 115/387 (30%) had stage IV disease. 153 (56%) HRD+ stage III pts and 61 (53%) HRD+ stage IV pts had a tBRCAm. Among HRD+ stage III pts, 172 (63%) had upfront surgery (51/172 [30%] had residual disease) and 90 (33%) had interval surgery (19/90 [21%] had residual disease); 52 (45%) HRD+ stage IV pts had upfront surgery (34/52 [65%] had residual disease) and 55 (48%) had interval surgery (18/55 [33%] had residual disease). Median follow-up for PFS and PFS2 was respectively 24.8 and 37.2 mo in HRD+ stage III pts and 24.0 and 37.0 mo in HRD+ stage IV pts. Median PFS, PFS2 and HRs are in the Table. Among HRD+ stage III pts, 36-mo PFS2 (olaparib + bev vs pbo + bev) was 74% vs 60%; among HRD+ stage IV pts, 53% vs 30%. Among HRD+ stage III pts with no residual disease after upfront surgery, HR (95% CI) for PFS was 0.15 (0.07–0.30) and for PFS2 was 0.22 (0.06–0.67). Among HRD+ stage III pts with residual disease after upfront surgery or who received neoadjuvant chemotherapy, or HRD+ stage IV pts, HR (95% CI) for PFS was 0.38 (0.27–0.53) and PFS2 was 0.68 (0.46–1.03). Conclusions: In the PAOLA-1 study, maintenance olaparib + bev provided a PFS and PFS2 benefit over pbo + bev in HRD+ pts, irrespective of FIGO stage and residual disease after upfront surgery. Clinical trial information: NCT02477644. [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]

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