Rucaparib

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Robert L Coleman - One of the best experts on this subject based on the ideXlab platform.

  • 2 exploratory analysis of postprogression and patient centered outcomes in ariel3 a phase 3 randomized placebo controlled study of Rucaparib maintenance treatment in patients with recurrent ovarian carcinoma
    International Journal of Gynecological Cancer, 2019
    Co-Authors: Robert L Coleman, Ana Oaknin, D Lorusso, Carol Aghajanian, A Dean, N Colombo, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Alexandra Leary
    Abstract:

    Objectives In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo. A prespecified exploratory analysis investigated postprogression outcomes. Additionally, a post hoc exploratory analysis investigated patient-centered outcomes during Rucaparib maintenance treatment. Methods Patients were randomized 2:1 to receive oral Rucaparib (600 mg BID) or placebo. Postprogression endpoints included time to start of first subsequent therapy (TFST), time to second investigator-assessed PFS or death (PFS2), and time to start of second subsequent therapy (TSST); overall survival data are not yet mature. Patient-centered outcomes included quality-adjusted investigator-assessed PFS (QA-PFS) and quality-adjusted progression-free time without symptoms or toxicity (Q-TWiST). Analyses are presented for the predefined BRCA-mutant cohort and the intent-to-treat (ITT) population. Results The visit cutoff dates for efficacy and safety were April 15, 2017, and December 31, 2017, respectively. Postprogression and patient-centered outcome data are given in the table 1. The most common treatment-emergent adverse events (TEAEs) of any grade (Rucaparib vs placebo) were nausea (75.8% vs 36.5%), asthenia/fatigue (70.7% vs 44.4%), dysgeusia (39.8% vs 6.9%), and anemia/decreased hemoglobin (39.0% vs 5.3%). Any grade TEAEs of nausea, asthenia/fatigue, and anemia/decreased hemoglobin led to discontinuation in only 2.7%, 1.6%, and 2.7% of Rucaparib-treated patients. Conclusions Rucaparib significantly improved clinically meaningful postprogression outcomes vs placebo in the BRCA-mutant cohort and ITT population. The quality-adjusted analyses, which incorporated patient-centered perspectives during Rucaparib maintenance treatment, confirmed the benefit of Rucaparib vs placebo. The updated safety profile of Rucaparib in ARIEL3 was consistent with prior reports.

  • Abstract CT158: ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of Rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer
    Cancer Research, 2019
    Co-Authors: Shannon Neville Westin, Rebecca Kristeleit, Ana Oaknin, Robert L Coleman, David M. O'malley, Keiichi Fujiwara, Thomas J Herzog, Frederik Marme, Ramez N Eskander
    Abstract:

    Background: The poly(ADP-ribose) polymerase (PARP) inhibitor Rucaparib has demonstrated clinical activity in patients with ovarian cancer with or without homologous recombination (HR) deficiency (HRD; eg, a BRCA mutation or high genome-wide loss of heterozygosity [LOH high]). ATHENA (NCT03522246) is evaluating Rucaparib + the anti-PD-1 antibody nivolumab as maintenance treatment following front-line platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for evaluating this combination includes the following: tumors with a deleterious BRCA mutation express novel, tumor-specific protein sequences (neoantigens), which can attract PD-L1-expressing, tumor-infiltrating lymphocytes; ovarian tumors with HRD have more neoantigens relative to HR-proficient tumors and may respond preferentially to immune checkpoint inhibitors; and Rucaparib combined with anti-PD-1 or anti-PD-L1 demonstrated improved antitumor activity in a syngeneic ovarian cancer BrKras ( BRCA1 -/- ; TP53 -/- ; MYC; KRAS-G12D; AKT ) model. Furthermore, it is hypothesized that DNA damage induced by PARP inhibition may increase neoantigens regardless of HRD status. Methods: Eligible patients must have completed first-line platinum doublet chemotherapy and surgery. Patients had to have achieved an investigator-assessed response without disease progression or rising CA-125 at any time during first-line platinum doublet treatment. Cytoreductive surgery (R0 permitted) could have been completed either prior to chemotherapy (primary surgery) or following neoadjuvant chemotherapy (interval debulking). Patients will be randomized 4:4:1:1 to receive maintenance treatment in Arm A (oral Rucaparib 600 mg BID + intravenous [IV] nivolumab 480 mg on day 1 of every 4-week cycle), Arm B (oral Rucaparib + IV placebo), Arm C (oral placebo + IV nivolumab), or Arm D (oral placebo + IV placebo). Stratification factors include centrally determined tumor HRD status ( BRCA mutant, non- BRCA mutant/LOH high, non- BRCA mutant/LOH low, or non- BRCA mutant/LOH indeterminate), posttreatment disease status (residual vs no residual disease), and timing of surgery (primary vs interval debulking). The primary endpoint of investigator-assessed progression-free survival (per RECIST version 1.1) will be evaluated in 3 independent comparisons between arms: A vs B, A vs D, and B vs D. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, investigator-assessed objective response rate, investigator-assessed duration of response, and safety. Enrollment is ongoing; patients (n≈1000) will be enrolled at >270 sites worldwide. Citation Format: Shannon N. Westin, Rebecca S. Kristeleit, Robert L. Coleman, Keiichi Fujiwara, Amit M. Oza, David M. O’Malley, Thomas J. Herzog, Frederik Marme, Ana Oaknin, Ramez Eskander, Domenica Lorusso, Tamar Safra, Jacob Korach, Kevin K. Lin, Danny Shih, Lisa Caunt, Sandra Goble, Stephanie Hume, Lara Maloney, Iain McNeish, Bradley J. Monk. ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of Rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT158.

  • abstract ct158 athena gog 3020 engot ov45 a randomized double blind placebo controlled phase iii study of Rucaparib nivolumab following front line platinum based chemotherapy in ovarian cancer
    Cancer Research, 2019
    Co-Authors: Shannon Neville Westin, Rebecca Kristeleit, Ana Oaknin, Robert L Coleman, David M Omalley, Keiichi Fujiwara, Thomas J Herzog, Frederik Marme, Ramez N Eskander, Domenica Lorusso
    Abstract:

    Background: The poly(ADP-ribose) polymerase (PARP) inhibitor Rucaparib has demonstrated clinical activity in patients with ovarian cancer with or without homologous recombination (HR) deficiency (HRD; eg, a BRCA mutation or high genome-wide loss of heterozygosity [LOH high]). ATHENA (NCT03522246) is evaluating Rucaparib + the anti-PD-1 antibody nivolumab as maintenance treatment following front-line platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for evaluating this combination includes the following: tumors with a deleterious BRCA mutation express novel, tumor-specific protein sequences (neoantigens), which can attract PD-L1-expressing, tumor-infiltrating lymphocytes; ovarian tumors with HRD have more neoantigens relative to HR-proficient tumors and may respond preferentially to immune checkpoint inhibitors; and Rucaparib combined with anti-PD-1 or anti-PD-L1 demonstrated improved antitumor activity in a syngeneic ovarian cancer BrKras ( BRCA1 -/- ; TP53 -/- ; MYC; KRAS-G12D; AKT ) model. Furthermore, it is hypothesized that DNA damage induced by PARP inhibition may increase neoantigens regardless of HRD status. Methods: Eligible patients must have completed first-line platinum doublet chemotherapy and surgery. Patients had to have achieved an investigator-assessed response without disease progression or rising CA-125 at any time during first-line platinum doublet treatment. Cytoreductive surgery (R0 permitted) could have been completed either prior to chemotherapy (primary surgery) or following neoadjuvant chemotherapy (interval debulking). Patients will be randomized 4:4:1:1 to receive maintenance treatment in Arm A (oral Rucaparib 600 mg BID + intravenous [IV] nivolumab 480 mg on day 1 of every 4-week cycle), Arm B (oral Rucaparib + IV placebo), Arm C (oral placebo + IV nivolumab), or Arm D (oral placebo + IV placebo). Stratification factors include centrally determined tumor HRD status ( BRCA mutant, non- BRCA mutant/LOH high, non- BRCA mutant/LOH low, or non- BRCA mutant/LOH indeterminate), posttreatment disease status (residual vs no residual disease), and timing of surgery (primary vs interval debulking). The primary endpoint of investigator-assessed progression-free survival (per RECIST version 1.1) will be evaluated in 3 independent comparisons between arms: A vs B, A vs D, and B vs D. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, investigator-assessed objective response rate, investigator-assessed duration of response, and safety. Enrollment is ongoing; patients (n≈1000) will be enrolled at >270 sites worldwide. Citation Format: Shannon N. Westin, Rebecca S. Kristeleit, Robert L. Coleman, Keiichi Fujiwara, Amit M. Oza, David M. O’Malley, Thomas J. Herzog, Frederik Marme, Ana Oaknin, Ramez Eskander, Domenica Lorusso, Tamar Safra, Jacob Korach, Kevin K. Lin, Danny Shih, Lisa Caunt, Sandra Goble, Stephanie Hume, Lara Maloney, Iain McNeish, Bradley J. Monk. ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of Rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT158.

  • exploratory analysis of the effect of maintenance Rucaparib on postprogression outcomes in patients pts with platinum sensitive recurrent ovarian carcinoma oc and updated safety data from the phase 3 study ariel3
    Journal of Clinical Oncology, 2019
    Co-Authors: Robert L Coleman, Ana Oaknin, Carol Aghajanian, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Domenica Lorusso, Andrew Peter Dean, Nicoletta Colombo, Alexandra Leary
    Abstract:

    5522Background: In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined, nested cohorts: BRCA mutation; BRCA mutation + wild-t...

  • Exploratory analysis of the effect of maintenance Rucaparib on postprogression outcomes in patients (pts) with platinum-sensitive recurrent ovarian carcinoma (OC) and updated safety data from the phase 3 study ARIEL3.
    Journal of Clinical Oncology, 2019
    Co-Authors: Robert L Coleman, Ana Oaknin, Carol Aghajanian, J I Weberpals, Andrew R Clamp, Domenica Lorusso, Andrew Peter Dean, Nicoletta Colombo, Giovanni Scambia
    Abstract:

    5522 Background: In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined, nested cohorts: BRCA mutation; BRCA mutation + wild-type BRCA/high loss of heterozygosity (LOH); and intent-to-treat (ITT) population. Methods: Pts were randomized 2:1 to receive oral Rucaparib 600 mg BID or placebo. Exploratory endpoints of time to first subsequent therapy (TFST), time to investigator-assessed PFS on the subsequent line of treatment or death (PFS2), and time to second subsequent therapy (TSST) were assessed in the predefined cohorts. Results: Exploratory efficacy endpoint data are given in the Table. As of Dec 31, 2017, the most common treatment-emergent adverse events (TEAEs) of any grade (Rucaparib vs placebo) were nausea (75.8% vs 36.5%), asthenia/fatigue (70.7% vs 44.4%), dysgeusia (39.8% vs 6.9%), and anemia/decreased hemoglobin (39.0% vs 5.3%). The most common grade ≥3 TEAEs were anemia/decreased hemoglobin (21.5% vs 0.5%) and alanine/aspartate aminotransferase increase (10.2% vs 0.0%). Conclusions: Rucaparib significantly improved the clinically meaningful endpoints TFST, PFS2, and TSST vs placebo in all predefined cohorts of pts with platinum-sensitive, recurrent OC. The updated safety profile was consistent with prior reports. Clinical trial information: NCT01968213. [Table: see text]

Ana Oaknin - One of the best experts on this subject based on the ideXlab platform.

  • Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.
    The Lancet. Oncology, 2020
    Co-Authors: Jonathan A Ledermann, Ana Oaknin, Carol Aghajanian, J I Weberpals, Andrew R Clamp, Domenica Lorusso, Nicoletta Colombo, Andrew Dean, Giovanni Scambia
    Abstract:

    In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral Rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to Rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the Rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with Rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the Rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the Rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths. In these exploratory analyses over a median follow-up of more than 2 years, Rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Clovis Oncology. Copyright © 2020 Elsevier Ltd. All rights reserved.

  • Rucaparib for patients with platinum sensitive recurrent ovarian carcinoma ariel3 post progression outcomes and updated safety results from a randomised placebo controlled phase 3 trial
    Lancet Oncology, 2020
    Co-Authors: Jonathan A Ledermann, Ana Oaknin, Carol Aghajanian, A Dean, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Domenica Lorusso, Nicoletta Colombo, Alexandra Leary
    Abstract:

    Summary Background In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. Methods In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral Rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov , NCT01968213 . Findings Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to Rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0–33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0–17·4) in the Rucaparib group versus 8·8 months (8·0–10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35–0·53]; p Interpretation In these exploratory analyses over a median follow-up of more than 2 years, Rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Funding Clovis Oncology.

  • real world delivery of Rucaparib to patients with ovarian cancer recommendations based on an integrated safety analysis of ariel2 and study 10
    Oncologist, 2020
    Co-Authors: Yvette Drew, Rebecca Kristeleit, Ana Oaknin, Isabelle Raycoquard, Noor Md Haris, Elizabeth M Swisher
    Abstract:

    Treatment options for women with recurrent ovarian cancer who have received two or more prior lines of chemotherapy have recently expanded with the U.S. Food and Drug Administration (FDA) and European Commission (EC) approvals of the poly(ADP-ribose) polymerase (PARP) inhibitor Rucaparib. As more oncologists begin to use Rucaparib and other PARP inhibitors as part of routine clinical practice, awareness of possible side effects and how to adequately manage toxicities is crucial. In this review, we summarize the safety and tolerability of Rucaparib reported in an integrated safety analysis that supported the FDA's initial approval of Rucaparib in the treatment setting. Additionally, drawing on clinical data and our personal experience with Rucaparib, we provide our recommendations on the management of common side effects observed with Rucaparib, including anemia, blood creatinine elevations, alanine aminotransferase and aspartate aminotransferase elevations, thrombocytopenia, gastrointestinal-related events (e.g., nausea, vomiting), and asthenia and fatigue. These side effects, many of which appear to be class effects of PARP inhibitors, are often self-limiting and can be managed with adequate interventions such as treatment interruption and/or dose reduction and the use of supportive therapies. Supportive therapies may include blood transfusions for patients with anemia, prophylactic medications to prevent nausea and vomiting, or behavioral interventions to mitigate fatigue. Understanding and appropriate management of potential side effects associated with Rucaparib may allow patients with ovarian cancer to continue to benefit from Rucaparib treatment. IMPLICATIONS FOR PRACTICE: Rucaparib was recently approved in the U.S. and European Union for use as treatment or maintenance for recurrent ovarian cancer. This review focuses on the safety and tolerability of Rucaparib in the treatment setting. Similar side effects are observed in the maintenance setting. Drawing on the authors' clinical experience with Rucaparib, Rucaparib prescribing information, and published supportive cancer care guidelines, this review discusses how to optimally manage common Rucaparib-associated side effects in patients with advanced ovarian cancer in the real-world oncology setting. Adequate management of such side effects is crucial for allowing patients with ovarian cancer to remain on treatment to receive optimal efficacy benefit.

  • Real‐World Delivery of Rucaparib to Patients with Ovarian Cancer: Recommendations Based on an Integrated Safety Analysis of ARIEL2 and Study 10
    Oncologist, 2019
    Co-Authors: Yvette Drew, Rebecca Kristeleit, Ana Oaknin, Noor Md Haris, Isabelle Ray-coquard, Elizabeth M Swisher
    Abstract:

    Treatment options for women with recurrent ovarian cancer who have received two or more prior lines of chemotherapy have recently expanded with the U.S. Food and Drug Administration (FDA) and European Commission (EC) approvals of the poly(ADP-ribose) polymerase (PARP) inhibitor Rucaparib. As more oncologists begin to use Rucaparib and other PARP inhibitors as part of routine clinical practice, awareness of possible side effects and how to adequately manage toxicities is crucial. In this review, we summarize the safety and tolerability of Rucaparib reported in an integrated safety analysis that supported the FDA's initial approval of Rucaparib in the treatment setting. Additionally, drawing on clinical data and our personal experience with Rucaparib, we provide our recommendations on the management of common side effects observed with Rucaparib, including anemia, blood creatinine elevations, alanine aminotransferase and aspartate aminotransferase elevations, thrombocytopenia, gastrointestinal-related events (e.g., nausea, vomiting), and asthenia and fatigue. These side effects, many of which appear to be class effects of PARP inhibitors, are often self-limiting and can be managed with adequate interventions such as treatment interruption and/or dose reduction and the use of supportive therapies. Supportive therapies may include blood transfusions for patients with anemia, prophylactic medications to prevent nausea and vomiting, or behavioral interventions to mitigate fatigue. Understanding and appropriate management of potential side effects associated with Rucaparib may allow patients with ovarian cancer to continue to benefit from Rucaparib treatment. IMPLICATIONS FOR PRACTICE: Rucaparib was recently approved in the U.S. and European Union for use as treatment or maintenance for recurrent ovarian cancer. This review focuses on the safety and tolerability of Rucaparib in the treatment setting. Similar side effects are observed in the maintenance setting. Drawing on the authors' clinical experience with Rucaparib, Rucaparib prescribing information, and published supportive cancer care guidelines, this review discusses how to optimally manage common Rucaparib-associated side effects in patients with advanced ovarian cancer in the real-world oncology setting. Adequate management of such side effects is crucial for allowing patients with ovarian cancer to remain on treatment to receive optimal efficacy benefit.

  • 2 exploratory analysis of postprogression and patient centered outcomes in ariel3 a phase 3 randomized placebo controlled study of Rucaparib maintenance treatment in patients with recurrent ovarian carcinoma
    International Journal of Gynecological Cancer, 2019
    Co-Authors: Robert L Coleman, Ana Oaknin, D Lorusso, Carol Aghajanian, A Dean, N Colombo, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Alexandra Leary
    Abstract:

    Objectives In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo. A prespecified exploratory analysis investigated postprogression outcomes. Additionally, a post hoc exploratory analysis investigated patient-centered outcomes during Rucaparib maintenance treatment. Methods Patients were randomized 2:1 to receive oral Rucaparib (600 mg BID) or placebo. Postprogression endpoints included time to start of first subsequent therapy (TFST), time to second investigator-assessed PFS or death (PFS2), and time to start of second subsequent therapy (TSST); overall survival data are not yet mature. Patient-centered outcomes included quality-adjusted investigator-assessed PFS (QA-PFS) and quality-adjusted progression-free time without symptoms or toxicity (Q-TWiST). Analyses are presented for the predefined BRCA-mutant cohort and the intent-to-treat (ITT) population. Results The visit cutoff dates for efficacy and safety were April 15, 2017, and December 31, 2017, respectively. Postprogression and patient-centered outcome data are given in the table 1. The most common treatment-emergent adverse events (TEAEs) of any grade (Rucaparib vs placebo) were nausea (75.8% vs 36.5%), asthenia/fatigue (70.7% vs 44.4%), dysgeusia (39.8% vs 6.9%), and anemia/decreased hemoglobin (39.0% vs 5.3%). Any grade TEAEs of nausea, asthenia/fatigue, and anemia/decreased hemoglobin led to discontinuation in only 2.7%, 1.6%, and 2.7% of Rucaparib-treated patients. Conclusions Rucaparib significantly improved clinically meaningful postprogression outcomes vs placebo in the BRCA-mutant cohort and ITT population. The quality-adjusted analyses, which incorporated patient-centered perspectives during Rucaparib maintenance treatment, confirmed the benefit of Rucaparib vs placebo. The updated safety profile of Rucaparib in ARIEL3 was consistent with prior reports.

Alexandra Leary - One of the best experts on this subject based on the ideXlab platform.

  • Rucaparib for patients with platinum sensitive recurrent ovarian carcinoma ariel3 post progression outcomes and updated safety results from a randomised placebo controlled phase 3 trial
    Lancet Oncology, 2020
    Co-Authors: Jonathan A Ledermann, Ana Oaknin, Carol Aghajanian, A Dean, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Domenica Lorusso, Nicoletta Colombo, Alexandra Leary
    Abstract:

    Summary Background In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. Methods In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral Rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov , NCT01968213 . Findings Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to Rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0–33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0–17·4) in the Rucaparib group versus 8·8 months (8·0–10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35–0·53]; p Interpretation In these exploratory analyses over a median follow-up of more than 2 years, Rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Funding Clovis Oncology.

  • 2 exploratory analysis of postprogression and patient centered outcomes in ariel3 a phase 3 randomized placebo controlled study of Rucaparib maintenance treatment in patients with recurrent ovarian carcinoma
    International Journal of Gynecological Cancer, 2019
    Co-Authors: Robert L Coleman, Ana Oaknin, D Lorusso, Carol Aghajanian, A Dean, N Colombo, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Alexandra Leary
    Abstract:

    Objectives In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo. A prespecified exploratory analysis investigated postprogression outcomes. Additionally, a post hoc exploratory analysis investigated patient-centered outcomes during Rucaparib maintenance treatment. Methods Patients were randomized 2:1 to receive oral Rucaparib (600 mg BID) or placebo. Postprogression endpoints included time to start of first subsequent therapy (TFST), time to second investigator-assessed PFS or death (PFS2), and time to start of second subsequent therapy (TSST); overall survival data are not yet mature. Patient-centered outcomes included quality-adjusted investigator-assessed PFS (QA-PFS) and quality-adjusted progression-free time without symptoms or toxicity (Q-TWiST). Analyses are presented for the predefined BRCA-mutant cohort and the intent-to-treat (ITT) population. Results The visit cutoff dates for efficacy and safety were April 15, 2017, and December 31, 2017, respectively. Postprogression and patient-centered outcome data are given in the table 1. The most common treatment-emergent adverse events (TEAEs) of any grade (Rucaparib vs placebo) were nausea (75.8% vs 36.5%), asthenia/fatigue (70.7% vs 44.4%), dysgeusia (39.8% vs 6.9%), and anemia/decreased hemoglobin (39.0% vs 5.3%). Any grade TEAEs of nausea, asthenia/fatigue, and anemia/decreased hemoglobin led to discontinuation in only 2.7%, 1.6%, and 2.7% of Rucaparib-treated patients. Conclusions Rucaparib significantly improved clinically meaningful postprogression outcomes vs placebo in the BRCA-mutant cohort and ITT population. The quality-adjusted analyses, which incorporated patient-centered perspectives during Rucaparib maintenance treatment, confirmed the benefit of Rucaparib vs placebo. The updated safety profile of Rucaparib in ARIEL3 was consistent with prior reports.

  • exploratory analysis of the effect of maintenance Rucaparib on postprogression outcomes in patients pts with platinum sensitive recurrent ovarian carcinoma oc and updated safety data from the phase 3 study ariel3
    Journal of Clinical Oncology, 2019
    Co-Authors: Robert L Coleman, Ana Oaknin, Carol Aghajanian, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Domenica Lorusso, Andrew Peter Dean, Nicoletta Colombo, Alexandra Leary
    Abstract:

    5522Background: In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined, nested cohorts: BRCA mutation; BRCA mutation + wild-t...

  • abstract pr06 ariel3 a phase 3 randomized double blind study of Rucaparib vs placebo following response to platinum based chemotherapy for recurrent ovarian cancer oc
    Clinical Cancer Research, 2018
    Co-Authors: Robert L Coleman, Ana Oaknin, Carol Aghajanian, A Dean, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Domenica Lorusso, Nicoletta Colombo, Alexandra Leary
    Abstract:

    Background: Rucaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved in the United States for treatment of women with deleterious BRCA mutation (germline and/or somatic) associated advanced OC who have been treated with two or more chemotherapies. Rucaparib has also demonstrated antitumor activity in the treatment setting in patients (pts) with BRCA wild-type associated recurrent OC whose tumor has high genomic loss of heterozygosity (LOH). ARIEL3 evaluated Rucaparib vs placebo as maintenance treatment in pts with recurrent platinum-sensitive OC. Methods: Eligible pts received ≥2 prior platinum-based therapies, had platinum-sensitive OC (disease progression ≥6 mo after penultimate platinum), and achieved a complete response (RECIST v1.1) or partial response (RECIST v1.1 or Gynecologic Cancer InterGroup CA-125 criteria) to their most recent platinum. All pts were required to have CA-125 less than the upper limit of normal. Pts were randomized 2:1 to receive oral Rucaparib 600 mg BID or placebo. Investigator-assessed progression-free survival (PFS) (primary endpoint) was assessed in a step-down procedure for 3 nested cohorts: (1) BRCA mutant (deleterious germline or somatic BRCA mutation); (2) homologous recombination deficient (HRD) (BRCA mutant or BRCA wild type/LOH high); and (3) intent-to-treat (ITT) population. PFS was also assessed by blinded independent central review (BICR) (secondary endpoint) and LOH status in pts with BRCA wild type OC (exploratory endpoint). Adverse events (AEs) were summarized descriptively. Results: ARIEL3 enrolled 564 pts (375, Rucaparib; 189, placebo). Nearly 200 pts (n=196) had BRCA mutation-associated OC. Of these pts, 130 had a germline BRCA mutation (82 [21.9%], Rucaparib; 48 [25.4%], placebo), 56 had a somatic BRCA mutation (40 [10.7%], Rucaparib; 16 [8.5%], placebo), and 10 pts had tumors with germline and/or somatic BRCA status unknown (8 [2.1%], Rucaparib; 2 [1.1%], placebo). Median investigator-assessed PFS in the BRCA-mutant cohort (130, Rucaparib; 66 placebo) was 16.6 mo vs 5.4 mo (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.16-0.34; P Conclusion: Rucaparib significantly improved PFS vs placebo in pts with platinum-sensitive, recurrent OC in all primary analysis groups of pts with platinum-sensitive, recurrent OC. Additionally, Rucaparib significantly improved PFS vs placebo in pts with BRCA wild-type OC (LOH high and LOH low). Clinical trial identification: NCT01968213. This abstract is also being presented as Poster A47. Citation Format: Robert L. Coleman, Amit M. Oza, Domenica Lorusso, Carol Aghajanian, Ana Oaknin, Andrew Dean, Nicoletta Colombo, Johanne I. Weberpals, Andrew Clamp, Giovanni Scambia, Alexandra Leary, Robert W. Holloway, David M. O’Malley, Terri Cameron, Lara Maloney, Sandra Goble, Kevin Lin, James Sun, Heidi Giordano, Jonathan A. Ledermann. ARIEL3: A phase 3, randomized, double-blind study of Rucaparib vs placebo following response to platinum-based chemotherapy for recurrent ovarian cancer (OC). [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR06.

  • evaluation of Rucaparib in platinum sensitive recurrent ovarian carcinoma roc in patients pts with or without residual bulky disease at baseline in the ariel3 study
    Journal of Clinical Oncology, 2018
    Co-Authors: Carol Aghajanian, Ana Oaknin, Robert L Coleman, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Domenica Lorusso, Andrew Peter Dean, Nicoletta Colombo, Alexandra Leary
    Abstract:

    5537Background: In ARIEL3, pts were randomized 2:1 (oral Rucaparib 600 mg or placebo). Rucaparib significantly improved progression-free survival (PFS) vs placebo in all primary analysis groups (Co...

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  • Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trial.
    The Lancet. Oncology, 2020
    Co-Authors: Jonathan A Ledermann, Ana Oaknin, Carol Aghajanian, J I Weberpals, Andrew R Clamp, Domenica Lorusso, Nicoletta Colombo, Andrew Dean, Giovanni Scambia
    Abstract:

    In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral Rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT01968213. Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to Rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0-33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0-17·4) in the Rucaparib group versus 8·8 months (8·0-10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35-0·53]; p<0·0001), median TFST was 12·4 months (11·1-15·2) versus 7·2 months (6·4-8·6; HR 0·43 [0·35-0·52]; p<0·0001), median PFS2 was 21·0 months (18·9-23·6) versus 16·5 months (15·2-18·4; HR 0·66 [0·53-0·82]; p=0·0002), and median TSST was 22·4 months (19·1-24·5) versus 17·3 months (14·9-19·4; HR 0·68 [0·54-0·85]; p=0·0007). CFI, TFST, PFS2, and TSST were also significantly longer with Rucaparib than placebo in the BRCA-mutant and homologous recombination-deficient cohorts. The most frequent treatment-emergent adverse event of grade 3 or higher was anaemia or decreased haemoglobin (80 [22%] patients in the Rucaparib group vs one [1%] patient in the placebo group). Serious treatment-emergent adverse events were reported in 83 (22%) patients in the Rucaparib group and 20 (11%) patients in the placebo group. Two treatment-related deaths have been previously reported in this trial; there were no new treatment-related deaths. In these exploratory analyses over a median follow-up of more than 2 years, Rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Clovis Oncology. Copyright © 2020 Elsevier Ltd. All rights reserved.

  • Rucaparib for patients with platinum sensitive recurrent ovarian carcinoma ariel3 post progression outcomes and updated safety results from a randomised placebo controlled phase 3 trial
    Lancet Oncology, 2020
    Co-Authors: Jonathan A Ledermann, Ana Oaknin, Carol Aghajanian, A Dean, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Domenica Lorusso, Nicoletta Colombo, Alexandra Leary
    Abstract:

    Summary Background In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival versus placebo. Here, we report prespecified, investigator-assessed, exploratory post-progression endpoints and updated safety data. Methods In this ongoing (enrolment complete) randomised, placebo-controlled, phase 3 trial, patients aged 18 years or older who had platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least two previous platinum-based chemotherapy regimens and responded to their last platinum-based regimen were randomly assigned (2:1) to oral Rucaparib (600 mg twice daily) or placebo in 28-day cycles using a computer-generated sequence (block size of six with stratification based on homologous recombination repair gene mutation status, progression-free interval following penultimate platinum-based regimen, and best response to most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary endpoint of investigator-assessed progression-free survival has been previously reported. Prespecified, exploratory outcomes of chemotherapy-free interval (CFI), time to start of first subsequent therapy (TFST), time to disease progression on subsequent therapy or death (PFS2), and time to start of second subsequent therapy (TSST) and updated safety were analysed (visit cutoff Dec 31, 2017). Efficacy analyses were done in all patients randomised to three nested cohorts: patients with BRCA mutations, patients with homologous recombination deficiencies, and the intention-to-treat population. Safety analyses included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov , NCT01968213 . Findings Between April 7, 2014, and July 19, 2016, 564 patients were enrolled and randomly assigned to Rucaparib (n=375) or placebo (n=189). Median follow-up was 28·1 months (IQR 22·0–33·6). In the intention-to-treat population, median CFI was 14·3 months (95% CI 13·0–17·4) in the Rucaparib group versus 8·8 months (8·0–10·3) in the placebo group (hazard ratio [HR] 0·43 [95% CI 0·35–0·53]; p Interpretation In these exploratory analyses over a median follow-up of more than 2 years, Rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Funding Clovis Oncology.

  • abstract ct158 athena gog 3020 engot ov45 a randomized double blind placebo controlled phase iii study of Rucaparib nivolumab following front line platinum based chemotherapy in ovarian cancer
    Cancer Research, 2019
    Co-Authors: Shannon Neville Westin, Rebecca Kristeleit, Ana Oaknin, Robert L Coleman, David M Omalley, Keiichi Fujiwara, Thomas J Herzog, Frederik Marme, Ramez N Eskander, Domenica Lorusso
    Abstract:

    Background: The poly(ADP-ribose) polymerase (PARP) inhibitor Rucaparib has demonstrated clinical activity in patients with ovarian cancer with or without homologous recombination (HR) deficiency (HRD; eg, a BRCA mutation or high genome-wide loss of heterozygosity [LOH high]). ATHENA (NCT03522246) is evaluating Rucaparib + the anti-PD-1 antibody nivolumab as maintenance treatment following front-line platinum-based chemotherapy in patients with newly diagnosed, high-grade ovarian, fallopian tube, or primary peritoneal cancer. The rationale for evaluating this combination includes the following: tumors with a deleterious BRCA mutation express novel, tumor-specific protein sequences (neoantigens), which can attract PD-L1-expressing, tumor-infiltrating lymphocytes; ovarian tumors with HRD have more neoantigens relative to HR-proficient tumors and may respond preferentially to immune checkpoint inhibitors; and Rucaparib combined with anti-PD-1 or anti-PD-L1 demonstrated improved antitumor activity in a syngeneic ovarian cancer BrKras ( BRCA1 -/- ; TP53 -/- ; MYC; KRAS-G12D; AKT ) model. Furthermore, it is hypothesized that DNA damage induced by PARP inhibition may increase neoantigens regardless of HRD status. Methods: Eligible patients must have completed first-line platinum doublet chemotherapy and surgery. Patients had to have achieved an investigator-assessed response without disease progression or rising CA-125 at any time during first-line platinum doublet treatment. Cytoreductive surgery (R0 permitted) could have been completed either prior to chemotherapy (primary surgery) or following neoadjuvant chemotherapy (interval debulking). Patients will be randomized 4:4:1:1 to receive maintenance treatment in Arm A (oral Rucaparib 600 mg BID + intravenous [IV] nivolumab 480 mg on day 1 of every 4-week cycle), Arm B (oral Rucaparib + IV placebo), Arm C (oral placebo + IV nivolumab), or Arm D (oral placebo + IV placebo). Stratification factors include centrally determined tumor HRD status ( BRCA mutant, non- BRCA mutant/LOH high, non- BRCA mutant/LOH low, or non- BRCA mutant/LOH indeterminate), posttreatment disease status (residual vs no residual disease), and timing of surgery (primary vs interval debulking). The primary endpoint of investigator-assessed progression-free survival (per RECIST version 1.1) will be evaluated in 3 independent comparisons between arms: A vs B, A vs D, and B vs D. Secondary endpoints include blinded independent central review of progression-free survival, overall survival, investigator-assessed objective response rate, investigator-assessed duration of response, and safety. Enrollment is ongoing; patients (n≈1000) will be enrolled at >270 sites worldwide. Citation Format: Shannon N. Westin, Rebecca S. Kristeleit, Robert L. Coleman, Keiichi Fujiwara, Amit M. Oza, David M. O’Malley, Thomas J. Herzog, Frederik Marme, Ana Oaknin, Ramez Eskander, Domenica Lorusso, Tamar Safra, Jacob Korach, Kevin K. Lin, Danny Shih, Lisa Caunt, Sandra Goble, Stephanie Hume, Lara Maloney, Iain McNeish, Bradley J. Monk. ATHENA (GOG-3020/ENGOT-ov45): a randomized, double-blind, placebo-controlled, Phase III study of Rucaparib + nivolumab following front-line platinum-based chemotherapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT158.

  • Exploratory analysis of the effect of maintenance Rucaparib on postprogression outcomes in patients (pts) with platinum-sensitive recurrent ovarian carcinoma (OC) and updated safety data from the phase 3 study ARIEL3.
    Journal of Clinical Oncology, 2019
    Co-Authors: Robert L Coleman, Ana Oaknin, Carol Aghajanian, J I Weberpals, Andrew R Clamp, Domenica Lorusso, Andrew Peter Dean, Nicoletta Colombo, Giovanni Scambia
    Abstract:

    5522 Background: In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined, nested cohorts: BRCA mutation; BRCA mutation + wild-type BRCA/high loss of heterozygosity (LOH); and intent-to-treat (ITT) population. Methods: Pts were randomized 2:1 to receive oral Rucaparib 600 mg BID or placebo. Exploratory endpoints of time to first subsequent therapy (TFST), time to investigator-assessed PFS on the subsequent line of treatment or death (PFS2), and time to second subsequent therapy (TSST) were assessed in the predefined cohorts. Results: Exploratory efficacy endpoint data are given in the Table. As of Dec 31, 2017, the most common treatment-emergent adverse events (TEAEs) of any grade (Rucaparib vs placebo) were nausea (75.8% vs 36.5%), asthenia/fatigue (70.7% vs 44.4%), dysgeusia (39.8% vs 6.9%), and anemia/decreased hemoglobin (39.0% vs 5.3%). The most common grade ≥3 TEAEs were anemia/decreased hemoglobin (21.5% vs 0.5%) and alanine/aspartate aminotransferase increase (10.2% vs 0.0%). Conclusions: Rucaparib significantly improved the clinically meaningful endpoints TFST, PFS2, and TSST vs placebo in all predefined cohorts of pts with platinum-sensitive, recurrent OC. The updated safety profile was consistent with prior reports. Clinical trial information: NCT01968213. [Table: see text]

  • exploratory analysis of the effect of maintenance Rucaparib on postprogression outcomes in patients pts with platinum sensitive recurrent ovarian carcinoma oc and updated safety data from the phase 3 study ariel3
    Journal of Clinical Oncology, 2019
    Co-Authors: Robert L Coleman, Ana Oaknin, Carol Aghajanian, J I Weberpals, Andrew R Clamp, Giovanni Scambia, Domenica Lorusso, Andrew Peter Dean, Nicoletta Colombo, Alexandra Leary
    Abstract:

    5522Background: In ARIEL3, Rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo in all predefined, nested cohorts: BRCA mutation; BRCA mutation + wild-t...

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  • evaluation of in vitro absorption distribution metabolism and excretion and assessment of drug drug interaction of Rucaparib an orally potent poly adp ribose polymerase inhibitor
    Xenobiotica, 2020
    Co-Authors: Mingxiang Liao, Jeri Beltman, Thomas C Harding, Andrew Simmons, Sarah S Jawtsai, Jim J Xiao
    Abstract:

    1. The absorption, distribution, metabolism, elimination, and drug-drug interaction (DDI) potential of the poly(ADP-ribose) polymerase (PARP) inhibitor Rucaparib was characterised in vitro.2. Rucap...

  • abstract 3888 intracranial evaluation of the in vivo pharmacokinetics brain distribution and efficacy of Rucaparib inbrca mutant triple negative breast cancer
    Cancer Research, 2019
    Co-Authors: Minh Ly Nguyen, Liliane Robillard, Thomas C Harding, Andrew Simmons, Jim J Xiao, Hartmut Kristeleit, Michelle Liao
    Abstract:

    Background: The poly(ADP-ribose) polymerase inhibitor Rucaparib is approved for use in recurrent ovarian cancer; however, there are limited data on the activity of Rucaparib in patients with central nervous system (CNS) involvement. The goals of these studies were to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of Rucaparib and to correlate these results with the efficacy observed in a BRCA1-mutant xenograft model of triple-negative breast cancer (TNBC). In addition, a case report where Rucaparib demonstrated clinical activity in the CNS of a patient with BRCA2-mutant breast cancer is presented. Methods and Results: In a PK study in CD-1 mice, Rucaparib demonstrated limited brain penetration after a single oral dose of 150 mg/kg, with a mean free brain-to-plasma AUC ratio (Kpuu, brain) of 0.09. The free brain Cmax of Rucaparib was 8.59 ng/mL, which was comparable to its free cerebrospinal fluid Cmax (6.69 ng/mL) but significantly lower than the total Cmax measured in the brain (118 ng/mL). The antitumor efficacy of Rucaparib was evaluated in orthotopic and intracranial tumor models using the BRCA1-mutant MDA-MB-436 TNBC cell line. In the orthotopic setting, Rucaparib ≥50 mg/kg BID resulted in >100% tumor growth inhibition (TGI) after 28 days of dosing. Higher levels of Rucaparib were observed in the tumor relative to plasma at all doses evaluated. A PK-PD analysis showed an inverse correlation between poly(ADP-ribose) and Rucaparib levels in the plasma and tumor, with decreased poly(ADP-ribose) levels correlating with greater TGI. To evaluate intracranial efficacy, a luciferase labelled MDA-MB-436 cell line was employed and tumor burden was evaluated by weekly bioluminescence measurements. Rucaparib 150 mg/kg BID demonstrated efficient suppression of tumor growth after 43 days of dosing, with >100% TGI. In support of these preclinical findings, a patient with germline BRCA2-mutant metastatic breast cancer who had progressive CNS disease following whole brain radiation therapy was treated with Rucaparib 600 mg PO BID for 9 months under a compassionate use program. A reduction of multiple metastatic brain lesions was observed based on MRI scans taken before and after Rucaparib treatment. The patient also experienced complete resolution of neurological symptoms. Conclusions: In vivo PK studies confirmed the limited brain penetration of Rucaparib in a murine model with an intact blood-brain barrier. Nevertheless, antitumor efficacy was observed in a BRCA1-mutant intracranial TNBC mouse model, and clinical activity has been observed in a patient with germline BRCA2-mutant breast cancer and CNS involvement who was treated with Rucaparib. Further studies are warranted to elucidate the activity of Rucaparib in the brain. Citation Format: Minh Nguyen, Liliane Robillard, Thomas C. Harding, Jim J. Xiao, Andrew D. Simmons, Hartmut Kristeleit, Michelle (Mingxiang) Liao. Intracranial evaluation of the in vivo pharmacokinetics, brain distribution, and efficacy of Rucaparib in BRCA-mutant, triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3888.

  • abstract 1716 the parp inhibitor Rucaparib activates the sting pathway and enhances antitumor responses of immune checkpoint inhibitors in brca deficient syngeneic models
    Cancer Research, 2018
    Co-Authors: Minh Ly Nguyen, Liliane Robillard, Thomas C Harding, Andrew Simmons
    Abstract:

    Background: The poly(ADP ribose) polymerase (PARP) inhibitor Rucaparib effectively kills homologous recombination (HR) deficient cells through impeding DNA repair that leads to DNA damage, apoptosis, and cell death. Detection of cytosolic DNA by the stimulator of interferon genes (STING) pathway mediates type I interferon (IFN) production and activates the immune system. Following Rucaparib treatment, the accumulation of damaged DNA in HR impaired tumors may elicit an immune response through STING signaling, and enhance Rucaparib activity as a single agent or in combination with immune checkpoint blockade. To test this hypothesis, Rucaparib efficacy and mechanism of action were evaluated using BRCA deficient syngeneic ovarian tumor models. Results: Single agent Rucaparib showed potent antitumor activity in the BRCA mut BrKras and ID8B3.15 models. In the BrKras model, Rucaparib treatment resulted in complete regression and prevented tumor formation upon re-challenge. However, this efficacy was abolished with anti-CD8 but not anti-CD4 depletion. CD8 tumor infiltrating lymphocytes (TILs) but not CD4 TILs increased with Rucaparib exposure, and expression profiling of Rucaparib treated tumors showed activation of the type I IFN pathway. In vitro PCR assays identified several targets that were upregulated upon Rucaparib treatment including Ccl5 and Cxcl10. Notably, increased Ccl5 and Cxcl10 levels were observed in BRCA mut cells but not in BRCA wt cells, and knockdown of the STING pathway genes MB21D1, IRF3, TBK1, and STING (TMEM173) abrogated Rucaparib induction of Ccl5 and Cxcl10. Furthermore, Rucaparib showed transcriptional activation of IFN type I signaling in BRCA mut reporter cells expressing the IFN stimulated response element consensus sequence driving luciferase expression, but required 6-fold higher concentrations in BRCA wt reporter cells. Similarly, a 10-fold higher Rucaparib dose was needed to inhibit proliferation of BRCA wt cells compared to BRCA mut cells in a cell viability assay. Consistent with the in vitro results, Rucaparib combined with anti-programmed death 1 or anti-programmed death ligand 1 therapy improved the survival and augmented antitumor responses in BRCA deficient syngeneic tumor models. Conclusions: Rucaparib treatment in HR deficient cells, and at a higher concentration in HR proficient cells, triggers type I IFN signaling through the STING pathway, which participates in the single agent efficacy of Rucaparib and enhances the combination of Rucaparib and checkpoint inhibitors in syngeneic models. These findings provide further evidence supporting the rationale for combining Rucaparib with checkpoint therapy for the treatment of patients with HR defective cancers. Citation Format: Minh Nguyen, Liliane Robillard, Kevin K. Lin, Thomas C. Harding, Andrew D. Simmons. The PARP inhibitor Rucaparib activates the STING pathway and enhances antitumor responses of immune checkpoint inhibitors in BRCA deficient syngeneic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1716.

  • efficacy and immune modulation of the tumor microenvironment with the combination of the parp inhibitor Rucaparib and cd122 biased agonist nktr 214
    Journal of Clinical Oncology, 2018
    Co-Authors: Andrew Simmons, Minh Ly Nguyen, Liliane Robillard, Thomas C Harding, Deborah H Charych
    Abstract:

    5582Background: NKTR-214 is a biased agonist of the IL2Rbg (CD122) pathway that activates and mobilizes CD8 T and NK cells into the tumor microenvironment. The PARP inhibitor Rucaparib has demonstr...

  • abstract 2475 in vitroandin vivoassessment of the mechanism of action of the parp inhibitor Rucaparib
    Cancer Research, 2017
    Co-Authors: Liliane Robillard, Thomas C Harding, Minh Nguyen, Andrew Simmons
    Abstract:

    Background: Rucaparib (CO-338) is an oral small molecule inhibitor of poly (ADP-ribose) polymerase (PARP) that is being developed for patients with BRCA1 and BRCA2 mutated and homologous recombination deficient ovarian cancer (Swisher et al., 2016; Lancet Oncol. Epub). The mechanism of action (MOA) of Rucaparib was characterized in the studies reported here. Methods: Enzymatic and cellular reporter assay profiling were performed by BPS Biosciences. Rucaparib potency was assessed using 6-day cell viability assays (CellTiter-Glo). In vivo PK/PD and efficacy studies in the MDA-MB-436 (BRCA1 mutant) and the HBCx-17 (BRCA2 mutant) TNBC models were performed at Crown Biosciences and XenTech, respectively. Results: In biochemical assays Rucaparib inhibited PARP-1, PARP-2 and PARP-3, with IC50 values of 0.8, 0.5, and 28 nM, respectively. Rucaparib weakly inhibited PARP5a (tankyrase 1[TNKS1]) and PARP5b (tankyrase 2[TNKS2]) with an IC50 of 796 and 486 nM; however Rucaparib did not inhibit TNKS1/2 in a cellular reporter assay evaluating Wnt pathway signaling (IC50 >10 µM). Rucaparib cytotoxicity was evaluated in the BRCA1 mutant (UWB1.289) and wild-type (UWB1.289+BRCA1) isogenic pair, and a panel (n=26) of breast and ovarian cancer cell lines. The UWB1.289 cell line was more sensitive to Rucaparib (IC50 = 375 nM) than the UWB1.289+BRCA1 cell line (IC50 = 5430 nM). Rucaparib also decreased the cell viability of several BRCA1 and BRCA2 mutant ovarian and breast cancer cell lines. Mechanistic analyses in the UWB1.289 cell line demonstrated a dose dependent decrease in poly (ADP) ribosylation (PAR; IC50 = 2.8 nM), and an increase in DNA damage and apoptosis. Taken together, these results are consistent with the concept of synthetic lethality, where simultaneous inhibition of multiple DNA repair pathways results in irreparable DNA damage and cell death. In vivo PK/PD and efficacy studies assessed the MOA and activity of Rucaparib in the MDA-MD-436 (BRCA1 mutant) xenograft model. In a PK/PD study, dose dependent inhibition of PAR was observed in the tumors of mice treated with 15, 50 and 150 mg/kg BID Rucaparib, resulting in statistically significant (p 2-fold) than the levels of Rucaparib measured in plasma. Dose dependent and statistically significant tumor growth inhibition was observed in both subcutaneous and orthotopic xenograft studies evaluating the anti-tumor activity of Rucaparib in the MDA-MB-436 model. Rucaparib also demonstrated potent activity in the BRCA2 mutant HBCx-17 patient-derived xenograft model. Conclusion: These results demonstrate that Rucaparib is a potent and selective inhibitor of PARP1, PARP-2, and PARP-3 with in vitro and in vivo activity in BRCA1/2 deficient tumors. Citation Format: Liliane Robillard, Minh Nguyen, Thomas C. Harding, Andrew D. Simmons. In vitro and in vivo assessment of the mechanism of action of the PARP inhibitor Rucaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2475. doi:10.1158/1538-7445.AM2017-2475

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