Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer

Abstract Background: Rucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers. Methods: Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0–1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles. Results: Rucaparib was well tolerated in patients up to doses of 480 mg per day and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, with a median duration of response of 179 days (range 84–567 days). Conclusions: Rucaparib is well tolerated and results in high levels of PARP inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is active in gBRCA-mutant ovarian cancer and this activity correlates with platinum-free interval. The key lessons learned from this study is that continuous rucaparib dosing is required for optimal response, the recommended phase 2 dose (RP2D) for continuous oral scheduling has not been established and requires further exploration and, thirdly, the use of a PD biomarker to evaluate dose–response has its limitations.

Download Full-text

Erratum: Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer

British Journal of Cancer ◽

10.1038/bjc.2016.133 ◽

2016 ◽

Vol 114 (12) ◽

pp. e21-e21 ◽

Cited By ~ 15

Author(s):

Yvette Drew ◽

Jonathan Ledermann ◽

Geoff Hall ◽

Daniel Rea ◽

Ros Glasspool ◽

...

Keyword(s):

Breast Cancer ◽

Multicentre Trial ◽

Brca Mutation ◽

Phase 2 ◽

Mutation Carriers ◽

Brca Mutation Carriers ◽

Germline Brca Mutation ◽

Polymerase Inhibitor ◽

Continuous Dosing

Download Full-text

Recommendations and Choices for BRCA Mutation Carriers at Risk for Ovarian Cancer: A Complicated Decision

Cancers ◽

10.3390/cancers10020057 ◽

2018 ◽

Vol 10 (2) ◽

pp. 57 ◽

Cited By ~ 13

Author(s):

Kelsey Lewis ◽

Karen Lu ◽

Amber Klimczak ◽

Samuel Mok

Keyword(s):

Ovarian Cancer ◽

At Risk ◽

Brca Mutation ◽

Mutation Carriers ◽

Brca Mutation Carriers

Download Full-text

Cost Effectiveness of Risk-Reducing Mastectomy versus Surveillance in BRCA Mutation Carriers with a History of Ovarian Cancer

Annals of Surgical Oncology ◽

10.1245/s10434-017-5995-z ◽

2017 ◽

Vol 24 (11) ◽

pp. 3116-3123 ◽

Cited By ~ 5

Author(s):

Charlotte Gamble ◽

Laura J. Havrilesky ◽

Evan R. Myers ◽

Junzo P. Chino ◽

Scott Hollenbeck ◽

...

Keyword(s):

Ovarian Cancer ◽

Cost Effectiveness ◽

Brca Mutation ◽

Mutation Carriers ◽

Brca Mutation Carriers ◽

History Of ◽

Risk Reducing

Download Full-text

Factors Impacting on Decision-Making towards Prophylactic Surgeries in BRCA Mutation Carriers and Women with Familial Predisposition

Breast Care ◽

10.1159/000503370 ◽

2019 ◽

Vol 15 (3) ◽

pp. 253-259

Author(s):

Robin Segerer ◽

Clara Peschel ◽

Ulrike Kämmerer ◽

Sebastian Häussler ◽

Achim Wöckel ◽

...

Keyword(s):

Ovarian Cancer ◽

Decision Making ◽

Brca Mutation ◽

Prophylactic Surgery ◽

Sexual Life ◽

Familial Predisposition ◽

Emotional Factors ◽

Mutation Carriers ◽

Brca Mutation Carriers ◽

Psychological Predictor

Background/Objectives: BRCA mutation carriers and women at high risk of breast/ovarian cancer are faced with the intricate question to opt for prophylactic surgeries and/or a periodic screening. The aim of this study was therefore to identify objective and emotional factors that have an impact on the decision-making process. Methods: Ninety-five women with BRCA mutations or women at increased breast/ovarian cancer lifetime risk were counseled at our outpatient department and either opted for prophylactic surgery or periodic screening. To identify the psychological factors that could have influenced the decision-making, a standardized questionnaire was applied. Additionally, clinical data were collected and were reviewed by a personal talk. Results: Seventy-one of the patients opted for an increased surveillance only, 21 for prophylactic surgeries. Positive predictors for prophylactic surgeries were sociodemographic characteristics such as parity and objective variables such as verified mutation status. Hierarchical regression analysis revealed that the need for safety in health issues has been the only significant psychological predictor of surgery beyond the objective factors. Fear of surgical procedures, menopausal symptoms after surgery, loss of attractiveness, or fear of interferences with sexual life did not significantly affect decision-making. Conclusion: Decision-making towards prophylactic surgeries is influenced by objective but also emotional factors. Knowing that fear and anxiety also have an important impact on decision-making, distinct counselling about the procedures, the subsequent risk reduction as well as the psychological effects of prophylactic surgeries are essential.

Download Full-text

Breast Cancer Following Ovarian Cancer in BRCA Mutation Carriers

Gynecologic Oncology ◽

10.1016/j.ygyno.2019.11.064 ◽

2020 ◽

Vol 156 (3) ◽

pp. e14-e15

Author(s):

A.I. Nañez ◽

S. Langer ◽

C. Garcia ◽

C.B. Powell

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Brca Mutation ◽

Mutation Carriers ◽

Brca Mutation Carriers

Download Full-text

Pathologic findings at risk-reducing salpingo-oophorectomy in germline BRCA mutation carriers: Optimal age of bilateral RRSO.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13046 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e13046-e13046

Author(s):

Yong-Man Kim ◽

Shin-Wha Lee ◽

Young-jae Lee

Keyword(s):

Medical Center ◽

Metastatic Cancer ◽

Brca Mutation ◽

Brca1 Mutation ◽

Premalignant Lesions ◽

Mutation Carriers ◽

Brca 1 ◽

Brca Mutation Carriers ◽

Germline Brca Mutation ◽

Risk Reducing

e13046 Background: Most BRCA1/2 carriers do not undergo risk-reducing salpingo-oophorectomy (RRSO) by the recommended age of 40. Methods: We retrospectively reviewed breast cancer patients identified as BRCA mutation carriers who underwent RRSO at Asan Medical Center, Seoul, Korea, from 2013 to 2015. Both fallopian tubes of all cases were examined according to the SEE/FIM protocol and immunohistochemically (IHC) staining was performed when a precursor lesion was suspected. Results: RRSO was performed in 55 patients. The median age at RRSO was 44 years (32–73 years). Of the 36 patients with IHC staining, 7 showed p53 overexpression, 1 showed Ki-67 overexpression, 2 showed serous tubal intraepithelial carcinoma, 2 showed occult cancer, and 1 showed metastatic cancer of breast origin. All occult invasive cancer cases were tubal origin and detected in patients older than 40 years. The detection rate of premalignant lesions or cancer was 21.8% (12/55). Among patients who underwent RRSO under the age of 40, premalignant lesions were found only in BRCA 1 mutation carriers (40.0% vs 0%). In BRCA 2 mutation carriers, premalignant lesions were only detected in those older than 40 years of age, indicating the possible faster occurrence of premalignant lesions in BRCA1 mutation carriers. Conclusions: Many patients still tend to delay RRSO until after they are 40 years old. Our findings support the significance of RRSO before the age of 40 in germline BRCA mutation carriers, especially in BRCA 1 mutation carriers.

Download Full-text

Comparison of risk-reducing surgery in women with BRCA and non-BRCA ovarian cancer susceptibility genes.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1547 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1547-1547

Author(s):

Zachary Phillip Schwartz ◽

Mae Zakhour ◽

Andrew John Li ◽

Christine S. Walsh ◽

Bj Rimel ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Susceptibility ◽

Brca Mutation ◽

Susceptibility Genes ◽

Brca Mutations ◽

Cancer Susceptibility Genes ◽

Mutation Carriers ◽

Brca Mutation Carriers ◽

History Of ◽

Risk Reducing

1547 Background: Risk reducing gynecologic surgery (RRSO) is standard of care for women with BRCA mutations. The optimal management for women with non-BRCA ovarian cancer susceptibility mutations remains unclear. We sought to characterize the practice patterns for these women at our two institutions. Methods: Women with germline ovarian cancer susceptibility genes who had a RRSO were identified from 1/2000-1/2019 in an IRB approved study. All patients were asymptomatic with no suspicion for malignancy at time of RRSO. Clinico-pathologic characteristics were extracted from the medical records. Continuous variables were analyzed with Kruskal-Wallis and categorical variables analyzed with chi square and t-tests. Results: 152 BRCA1, 95 BRCA2, and 63 Non-BRCA mutation carriers were identified—50 Lynch (22 MLH1, 13 MSH2, 13 MSH6, 2 PMS2) and 13 Other (6 BRIP1, 2 RAD51C, 5 RAD51D). There was no difference between age at testing, age at RRSO, and interval between testing and RRSO between groups. Genetic counseling was higher in Non-BRCA patients. Family history of ovarian cancer was more common in women with BRCA1 and Other germline mutations compared to BRCA2 and Lynch. Family and personal history of breast cancer was high in all groups except Lynch carriers. Prophylactic mastectomy was seen mostly in BRCA mutation carriers. Concomitant hysterectomy was performed in the majority of women (BRCA1 59%, BRCA2 57%, and Other 62%), with the highest frequency in Lynch carriers (86%, p<.01). Occult cancer was only seen in BRCA mutation carriers: BRCA1 (7%), BRCA2 (2%), Lynch (0%), Other (0%). Conclusions: In this cohort, women with Non-BRCA mutations are managed similarly to women with BRCA mutations. We observed no occult cancers in Non-BRCA patients. The optimal role of surgery as a risk reducing strategy in this group requires further study. [Table: see text]

Download Full-text