Expert Review: The Role of PARP Inhibition in the Treatment of Breast Cancer Reference Slides
Overview
BRCA Mutations and Breast Cancer Patients with BRCA mutations have an estimated 55% to 65% cumulative risk of developing breast cancer by age 70 years 1,2 Germline mutations in BRCA1 and BRCA2 account for 5% to 10% of all female breast cancers, and 15% to 20% of all familial breast cancers 3-5 Mutations in BRCA1 are more frequently associated with TNBC, while mutations in BRCA2 are more commonly associated with estrogen receptor positive breast cancer 6,7 TNBC, triple negative breast cancer 1. Antoniou A, et al. Am J Hum Genet. 2003;72(5):1117-1130. 2. Chen S, et al. J Clin Oncol. 2007;25(11):1329-1333. 3. American Cancer Society. Breast Cancer Facts & Figures 2015-2016. Atlanta: American Cancer Society, Inc. 2015. 4. Schwartz GF, et al. Cancer. 2008;113(10):2627-2637. 5. Turnbull C, et al. Annu Rev Genomics Hum Genet. 2008;9:321-345. 6. Antoniou AC, et al. Breast Cancer Res. 2012;14(1):R33. 7. Mavaddat N, et al. Cancer Epidemiol Biomarkers Prev. 2012;21(1):134-147.
Characteristics Associated With an Increased Likelihood of a BRCA Mutation BRCA mutations are more likely to be found in: Patients with a family history of breast cancer Younger patients Patients younger than 60 years of age with TNBC Patients in certain ethnic groups, such as Ashkenazi Jews Bilateral breast cancer A history of both breast and ovarian cancer National Cancer Institute. Genetics of Breast and Gynecologic Cancers (PDQ ) Health Professional Version. www.cancer.gov/types/breast/hp/breastovarian-genetics-pdq#section/_88. Accessed October 3, 2017.
Which Patients With Breast Cancer Should Be Screened for a BRCA Mutation? Diagnosis at 45 years of age Diagnosis at 50 years of age with: An additional breast cancer primary 1 close blood relative with breast cancer at any age 1 close relative with pancreatic cancer 1 relative with prostate cancer (Gleason score 7) An unknown or limited family history Diagnosis 60 years of age with TNBC Diagnosis at any age with: 2 close blood relatives with breast, pancreatic, or prostate cancer (Gleason score 7) at any age 1 close relative with breast cancer diagnosed 50 years 1 close blood relative with ovarian carcinoma A close male blood relative with breast cancer An ethnicity associated with higher mutation frequency (eg, Ashkenazi Jew): For this patient, no additional family history may be required National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology : Genetic/Familial High-Risk Assessment: Breast and Ovarian. V2.2017. www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Accessed September 27, 2017.
Rationale PARP Inhibition in BRCA-Mutant Breast Cancer
Role of PARP in DNA Repair and Main Effects of PARP Inhibitors BER, base excision repair; NHEJ, non-homologous end joining; MMEJ, microhomology-mediated end joining Konecny GE, et al. Br J Cancer. 2016;115(10):1157-1173.
Synthetic Lethality in Tumors From BRCA Mutation Carriers Treated With PARP Inhibitors Polyak K, et al. Nature Med. 2011;17(3):283-284.
PARP Inhibitors in Phase III Development for BRCA-Mutant Breast Cancer Olaparib Talazoparib Veliparib Niraparib
PARP Inhibitors in Metastatic Breast Cancer
Olaparib
Phase II Studies of Olaparib in Breast Cancer Tutt, et al 1 (n = 54) Gelmon, et al 2 (n = 26, 10 gbrcam) Kaufman, et al 3 (n = 62) Patient Population Locally advanced/metastatic BRCAm BC, 1 chemotherapy regimen Advanced metastatic or recurrent BC, triple negative or known BRCAm Advanced BRCAm BC that progressed despite 3 previous lines of chemotherapy for advanced/metastatic BC Prior lines of therapy for advanced disease 3 (median, including adjuvant) 3 (median, including adjuvant) 4.6 (mean, metastatic only) ORR 41% 0% (5/10 [50%] unconfirmed PR in BRCAm) 13% Median DoR 144 days - 204 days BC, breast cancer; DoR, duration of response; ORR, objective response rate; PR, partial response 1. Tutt A, et al. Lancet. 2010;376(9737):235-244. 2. Gelmon KA, et al. Lancet Oncol. 2011;12(9):852-861. 3. Kaufman B, et al. J Clin Oncol. 2015;33(3):244-250. Robson M, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA4.
Treat until progression Phase III OlympiAD Trial: Olaparib in Patients With HER2-Negative MBC and a gbrca Mutation HER2-negative metastatic BC ER+ and/or PR+ or TNBC Deleterious or suspected deleterious gbrcam Prior anthracycline and taxane 2 prior chemotherapy lines in metastatic setting HR+ disease progressed on 1 endocrine therapy, or not suitable If prior platinum use No evidence of progression during treatment in the advanced setting 12 months since (neo)adjuvant treatment Olaparib 300 mg tablets bd 2:1 randomization Chemotherapy treatment of physician's choice (TPC) Capecitabine Eribulin Vinorelbine Primary endpoint: Progression-free survival (RECIST 1.1, BICR) Secondary endpoints: Time to second progression or death Overall survival Objective response rate Safety and tolerability Global HRQoL (EORTC-QLQ-C30) BICR, blinded independent central review; EORTC, European Organisation for the Research and Treatment of Cancer; ER, estrogen receptor; HRQoL, health-related quality of life; PR, progesterone receptor; RECIST, response evaluation criteria in solid tumors; TNBC, triple negative breast cancer Robson M, et al. N Engl J Med. 2017;377(6):523-533.
Progression-Free Survival, % Primary Endpoint: Progression-Free Survival Hazard ratio, 0.58 (95% CI, 0.43-0.80) P<.001 Months Since Randomization Robson M, et al. N Engl J Med. 2017;377(6):523-533.
Overall Survival, % Overall Survival Hazard ratio, 0.90 (95% CI, 0.63-1.29) P =.57 Months Since Randomization Robson M, et al. N Engl J Med. 2017;377(6):523-533.
Robson M, et al. N Engl J Med. 2017;377(6):523-533. Response Rate
Safety Summary: Adverse Events and Exposure n (%) Olaparib 300 mg bd (N = 205) Chemotherapy TPC (N = 91*) Grade 1-2 124 (60.5) 42 (46.2) Grade 3 75 (36.6) 46 (50.5) Death 1 (0.5) 1 (1.1) AEs leading to drug discontinuations 10 (4.9) 7 (7.7) AEs leading to dose reductions 52 (25.4) 28 (30.8) AEs leading to drug interruption/delay 72 (35.1) 25 (27.5) Median duration of treatment, months 8.2 (0.5-28.7) 3.4 (.07-23.0) *6 patients did not receive study treatment and are not evaluable for safety AE, adverse event; TPC, treatment of physician s choice Robson M, et al. N Engl J Med. 2017;377(6):523-533.
Adverse Events (Any Group) in 15% of Patients Nausea Anemia Vomiting Fatigue Neutropenia Diarrhea Headache Cough Decreased white blood cells Decreased appetite Pyrexia Increased ALT Increased AST Hand-foot syndrome Irrespective of causality. MedDRA preferred terms for AEs have been combined for 1) anemia and 2) neutropenia ALT, alanine aminotransferase; AST, aspartate aminotransferase Robson M, et al. N Engl J Med. 2017;377(6):523-533. 58 40 30 29 27 21 20 17 16 16 14 11 9 1 75 50 25 0 25 50 75 Adverse Events (%) 7 12 15 15 18 18 17 23 22 21 21 26 35 50 Olaparib 300 mg bd (N = 205) Chemotherapy TPC (N = 91)
Grade 3 Adverse Events in 2% of Patients in Either Arm Anemia Neutropenia Decreased white blood cells Fatigue Leukopenia Decreased platelet count Increased AST Dyspnea Headache Hand-foot syndrome 16 9 3 3 2 2 2 1 1 0 Olaparib 300 mg bd (N = 205) Chemotherapy TPC (N = 91) 75 50 25 0 25 50 75 1 3 1 0 4 3 2 2 10 Adverse Events (%) 26 Irrespective of causality. MedDRA preferred terms for AEs have been combined for 1) anemia and 2) neutropenia Robson M, et al. N Engl J Med. 2017;377(6):523-533.
Global Heath-Related Quality of Life (EORTC QLQ-C30 100-Point Scale*) Average Across All Study Visits Olaparib 300 mg bd (n = 191) Chemotherapy TPC (n = 73) Adjusted mean change (standard error) 3.9 (1.2) -3.6 (2.2) Estimated difference (95%) 7.5 (2.5 to 12.4) P =.0035 Only patients with baseline and 1 post-baseline assessment included *An increase in QOL score implies improvement in QOL and a decrease a deterioration Robson M, et al. N Engl J Med. 2017;377(6):523-533.
Talazoparib
Phase II ABRAZO Trial: Talazoparib Following Platinum or Multiple Cytotoxic Regimens in ABC With gbrca1/2 Mutations Patients with advanced breast cancer with a deleterious or suspected deleterious germline BRCA1/2 mutation (by central laboratory or a local report approved by the sponsor) Cohort 1: PR or CR to last platinum-containing regimen for metastatic disease with disease progression >8 weeks following last dose of platinum Cohort 2: Three or more prior cytotoxic regimens for metastatic disease; no prior platinum for metastatic disease Measurable disease by RECIST v1.1 ECOG performance status 0/1 and adequate organ and bone marrow function CNS metastases permitted, provided stable following local therapy HER2+ breast cancer permitted, provided the patient s disease was refractory to HER2-targeted therapy ABC, advanced breast cancer; CR, complete response Turner NC, et al. J Clin Oncol. 2017;35(suppl): Abstract 1007.
Primary Endpoint: Overall Response Rate Cohort 1 Prior Platinum (n = 48) Cohort 2 3L+, No Prior Platinum (n = 35) Total (N = 83) Objective response rate (ORR), % (95% CI) 21 (10-35) 37 (22-55) 28 (18-39) Best overall response, % (number) Complete response 4 (2) 0 2 (2) Partial response 17 (8) 37 (13) 25 (21) Stable disease 38 (18) 51 (18) 43 (36) Progressive disease 38 (18) 11 (4) 27 (22) Not evaluable 4 (2) 0 2 (2) Turner NC, et al. J Clin Oncol. 2017;35(suppl): Abstract 1007.
Number of patients 1 TEAE, % (number) Safety: Hematologic Cohort 1 Prior Platinum (n = 48) Cohort 2 3L+, No Prior Platinum (n = 35) All Grade Grade 3 Grade 4 All Grade Grade 3 Grade 4 68.8 (33) 52.1 (25) 6.3 (3) 74.3 (26) 48.6 (17) 11.4 (4) Anemia 50.0 (24) 33.3 (16) 0 54.3 (19) 37.1 (13) 0 Thrombocytopenia 37.5 (18) 16.7 (8) 4.2 (2) 25.7 (9) 11.4 (4) 5.7 (2) Neutropenia 20.8 (10) 12.5 (6) 0 34.3 (12) 17.1 (6) 0 Leukopenia 14.6 (7) 2.1 (1) 0 17.1 (6) 5.7 (2) 0 Platelet count decreased 14.6 (7) 6.3 (3) 2.1 (1) 14 (5) 2.9 (1) 5.7 (2) Transfusions: 1 patient with platelet transfusion, 23 patients (28%) with packed red blood cells Hemorrhage: 1 grade 3 hemorrhage (transient epistaxis) Neutropenic sepsis in 1 patient; 2 patients required growth factor support No acute myeloid leukemia or myelodysplastic syndrome All TEAEs in 15% of patients and grade 3+ TEAEs in 5% of patients TEAE, treatment-emergent adverse event Turner NC, et al. J Clin Oncol. 2017;35(suppl): Abstract 1007.
Number of patients 1 TEAE, % (number) Safety: Nonhematologic Cohort 1 Prior Platinum (n = 48) Cohort 2 3L+, No Prior Platinum (n = 35) All Grade Grade 3 Grade 4 All Grade Grade 3 Grade 4 97.9 (47) 22.9 (11) 4.2 (2) 97.1 (34) 28.6 (10) 2.9 (1) Fatigue 60.4 (29) 6.3 (3) 0 22.9 (8) 0 0 Nausea 41.7 (20) 4.2 (2) 0 42.9 (15) 0 0 Diarrhea 35.4 (17) 2.1 (1) 0 28.6 (10) 0 0 Decreased appetite 22.9 (11) 2.1 (1) 0 25.7 (9) 0 0 Dyspnea 22.9 (11) 2.1 (1) 2.1 (1) 25.7 (9) 5.7 (2) 0 Alopecia (grade 1) 22.9 (11) 0 0 20.0 (7) 0 0 Back pain 22.9 (11) 0 0 20.0 (7) 0 0 Vomiting 20.8 (10) 0 0 20.0 (7) 0 0 Pleural effusion 8.3 (4) 6.3 (3) 0 11.4 (4) 5.7 (2) 0 No grade 5 TEAEs were observed; no clinically significant cardiovascular toxicity All TEAEs in 20% of patients and grade 3+ TEAEs in 5% of patients Turner NC, et al. J Clin Oncol. 2017;35(suppl): Abstract 1007.
Phase III EMBRACA Trial Ongoing Open-label, randomized, 2-arm, international phase III trial Key Eligibility Advanced and/or metastatic breast cancer BRCA mutation by Myriad test 3 prior lines of therapy ECOG PS: 0-2 Randomize 2:1 N = up to 429 Open-label Talazoparib 1 mg qd, 21-day cycle Physician s choice, 21-day cycle Capecitabine Eribulin Gemcitabine Vinorelbine Follow for survival Stratification Factors Prior lines of therapy (0 vs 1, 2, or 3) TNBC vs non-tnbc History of CNS metastasis (yes vs no) Primary endpoint IRF-assessed mpfs per RECIST with modifications Secondary endpoints Overall survival (OS) IRF-assessed ORR Safety Pharmacokinetics Exploratory endpoints Duration of response QoL assessed by QLQ-C30 and QLQ-BR23 Blood and tumor biomarkers Protocol-specified physician s choice must be determined prior to randomization for each patient Treatment will continue until disease progression, unacceptable toxicity, consent withdrawal, physician s decision, or sponsor s decision to terminate the trial CNS, central nervous system; ECOG PS, Eastern Cooperative Oncology Group performance status; IRF, independent review facility; mpfs, median progression-free survival National Institute of Health. https://clinicaltrials.gov/ct2/show/nct01945775. Accessed October 3, 2017
Veliparib
Phase II BROCADE Trial: Veliparib in Combination With Carbo/Paclitaxel vs Placebo + Carbo/Paclitaxel in Pts With BRCA1 or BRCA2 Mutations and Locally Recurrent or Metastatic Breast Cancer Primary Endpoint: PFS Secondary: OS, CBR (week 18 progression-free rate), ORR *Carbo/paclitaxel administered on D3, 21-day cycle 28-day cycle Patients were treated until progression or unmanageable toxicity If both carboplatin and paclitaxel or if TMZ was discontinued, placebo/veliparib was discontinued Han HS, et al. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016: San Antonio, Texas. Abstract S2-5.
Progression-Free Survival Placebo + C/P N = 98 Veliparib + C/P N = 95 HR P Value Median PFS, months (95% CI) 12.3 (9.3-14.5) 14.1 (11.5-16.2) 0.789 (0.536-1.162).231 Han HS, et al. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016: San Antonio, Texas. Abstract S2-5.
Overall Survival Placebo + C/P N = 98 Veliparib + C/P N = 95 HR P Value Median OS, months (95% CI) 25.9 (20.4-31.8) 28.3 (24.9-NR) 0.750 (0.503-1.117).157 Han HS, et al. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016: San Antonio, Texas. Abstract S2-5.
Overall Response Rate Han HS, et al. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016: San Antonio, Texas. Abstract S2-5.
Treatment-Emergent Adverse Event Summary Han HS, et al. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016: San Antonio, Texas. Abstract S2-5.
Randomization 2:1 Phase III BROCADE3 Trial Ongoing Patient Population Women and men 18 years old Locally advanced (unresectable) or metastatic HER2- breast cancer Suspected deleterious or deleterious BRCA1 and BRCA2 germline mutation No more than 2 prior lines of DNA-damaging therapy for metastatic breast cancer No prior PARP inhibitors Stable CNS metastases N = 180 Pac/Carbo/Veliparib* Endpoints Primary Endpoints CNS metastases (yes vs no) Upon confirmation of progression, subjects randomized to placebo will have the option to receive single-agent veliparib therapy (crossover) ER, estrogen receptor; PR, progesterone receptor National Institute of Health. https://clinicaltrials.gov/ct2/show/nct02163694. Accessed October 3, 2017. N = 90 Pac/Carbo/Placebo* *If carboplatin and paclitaxel are discontinued for toxicity, veliparib/placebo will be continued as a single agent Stratification Factors for Randomization: ER and/or PR positives vs ER and PR negatives Prior platinum therapy (yes vs no) PFS Secondary Endpoints OS Clinical benefit rate ORR PFS2 Duration of overall response Tertiary Endpoints Change in ECOG PS Change in QoL
Niraparib
Phase III BRAVO Trial: Niraparib vs Treatment of Physician s Choice in HER2-Negative gbrca Mutated Advanced/Metastatic Breast Cancer Estimated enrollment: 306 Ongoing, but not recruiting Eligible Patients Open label, randomized (ratio 2:1) No crossover to niraparib is allowed Niraparib Total daily dose 300 mg Stratification factors: Visceral disease (yes or no) Histology (TNBC vs ER/PR positive) Number of lines of prior cytotoxic chemotherapy for metastatic breast cancer (0-1 v 2) Physician s choice Eribulin or Vinorelbine or Gemcitabine or Capecitabine National Institute of Health. https://clinicaltrials.gov/ct2/show/nct01905592. Accessed October 3, 2017.
PARP Inhibitors in Early Breast Cancer
Olaparib: Ongoing Phase III OlympiA Trial Age 18 years Patients with histologically confirmed, nonmetastatic primary cancer at high risk of recurrence, including postneoadjuvant, non-pcr patients or post-adjuvant patients with node-positive (any tumor size) or node-negative (primary tumor >2 cm) disease HER2 negative (not eligible for anti-her2 therapy)* Completed adequate breast and axilla surgery Completed 6 cycles of neoadjuvant or adjuvant chemotherapy containing anthracyclines, taxanes, or both Prior platinum as potentially curative treatment for prior cancer (eg, ovarian) or as adjuvant/neoadjuvant for breast cancer is allowed Randomization within 8 weeks of last treatment (surgery, chemotherapy, or radiotherapy) No investigational therapy within 30 days prior to randomization non-pcr No prior treatment with a PARP inhibitor Documented germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious ECOG PS 0 or 1 MRI, magnetic resonance imaging; pcr, pathologic complete response National Institute of Health. https://clinicaltrials.gov/ct2/show/nct02032823. Accessed October 3, 2017.
Phase III BrighTNess Trial: Veliparib Plus Carboplatin vs Addition of Carboplatin to Standard Neoadjuvant Therapy for Early-Stage TNBC Screening Day -28 Informed Consent Arm A Arm B Arm C Randomization 2:1:1 Segment 1 12-16 weeks Veliparib 50 mg BID + carboplatin + paclitaxel Placebo BID + carboplatin + paclitaxel Placebo BID + placebo + paclitaxel Segment 2 8-12 weeks Doxorubicin + cyclophosphamide Pre-op Visit a = First day of treatment with veliparib/placebo + carboplatin/placebo + paclitaxel = First day of treatment with veliparib/placebo + carboplatin/placebo + paclitaxel Surgery b Primary Endpoint: pcr Secondary Endpoints: EFS, OS, rate of eligibility for breast conservation after therapy among patients who were deemed ineligible at screening a Performed at least 2 weeks after last chemotherapy treatment b Surgery (+/- radiotherapy) was recommended approximately 2-8 weeks after last chemotherapy treatment pcr, pathologic complete response Geyer CE, et al. J Clin Oncol. 2017;35(suppl): Abstract 520.
Veliparib Phase III BrighTNess Trial of addition of veliparib plus carboplatin vs addition of carboplatin to standard neoadjuvant therapy for early-stage TNBC Addition of veliparib to neoadjuvant carboplatin + paclitaxel followed by AC did not increase pcr rate 100 75 P =.357 pcr P<.001 50 25 0 53.2 57.5 AC, doxorubicin + cyclophosphamide; Cb, carboplatin; P, paclitaxel; V, veliparib Geyer CE, et al. J Clin Oncol. 2017;35(suppl): Abstract 520. 31.0 V + Cb + P Cb + P P (n = 316) (n = 160) (n = 158)
prime Points
prime Points Olaparib is the first PARP inhibitor to show benefit over standard therapy for germline BRCA mutated metastatic breast cancer in a phase III trial; trial results with other PARP inhibitors are eagerly awaited Studies with PARP inhibitors are ongoing in the early breast cancer setting PARP inhibitors are generally well tolerated; adverse events are manageable Combinations of PARP inhibitors with other agents (ie, chemotherapy, targeted agents, immunotherapy) are under investigation