Optimizing DNA Damage Response- Targeting Therapies: Focus on Genetic Testing and Counseling

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2 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current as of May The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of Creative Educational Concepts or the supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.

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4 Optimizing DNA Damage Response- Targeting Therapies: Focus on Genetic Testing and Counseling

5 BRCA1/2 Mutations in Cancer BRCA1/2 mutations increase the risk for: Breast cancer EOC/FT/PPC Pancreatic cancer Prostate cancer BRCA2 more aggressive: Gleason score >7, higher stage, more risk metastatic disease BRCA2: Melanoma, biliary?/gastric? not part of criteria for testing NCCN Breast/Ovarian Genetic Assessment Guidelines Version

6 Who Should be Tested for BRCA1/2 Mutations? Ovarian Cancer All EOC/FT/PPC pts NCCN, ASCO, SGO guidelines agree Insurance cover appropriate pts NCCN Breast/Ovarian Genetic Assessment Guidelines Version ;

7 Who Should be Tested for BRCA1/2 Mutations? Breast Cancer Breast cancer diagnosis and any of the following: 45 yrs ( 50 yrs if small family/few women) TNBC 60 yrs Ashkenazi Jewish ancestry Male Bilateral 1 st 50 yrs 50 yrs: 1 relative with breast, pancreatic, or prostate cancer Any age: 2 relatives with breast, pancreatic, or prostate cancer 1 relative with ovarian cancer 1 relative with breast cancer diagnosed 50 yrs 1 male relative with breast cancer NCCN Breast/Ovarian Genetic Assessment Guidelines Version

8 Who Should be Tested for BRCA1/2 Mutations? Other Cancers Pancreatic or prostate cancer (Gleason score 7) and one of the following: 1 relative: Breast 50 yrs or ovarian cancer (any age) 2 relatives: Breast (any age), pancreatic, or prostate cancer Ashkenazi Jewish pancreatic cancer Family hx of BRCA1/2 mutation Somatic BRCA1/2 mutation identified in tumor NCCN Breast/Ovarian Genetic Assessment Guidelines Version

9 Why Do Genetic Testing of a Cancer Patient? Family members Identify other cancers to screen for/or prevent Treatment Platinum PARP Inhibitors

10 Why Do Genetic Testing of a Cancer Patient? Family members Identify other cancers to screen for/or prevent Treatment Platinum PARP Inhibitors

11 Somatic vs. Germline Mutations Somatic (Acquired) Mutations Occur in non-germline tissues Are not inherited Germline (Inherited) Mutations Present in egg or sperm Can be inherited from either parent Can cause cancer family syndrome Not Inheritable Inheritable Mutation only found in tumor Unaffected children Mutation in egg or sperm All cells affected in children Adapted from

12 Incidence of BRCA1/2 Germline (Inherited) Mutations Ovarian Cancer ~10-15% Breast Cancer ~3-4% (Overall) ~10-20% (TNBC) ~10-15% (Ashkenazi Jewish breast cancer) Pancreatic Cancer ~1-5% (Overall) 12% (Ashkenazi Jewish pancreatic cancer) Prostate Cancer ~1-2% (Overall) Metastatic: ~6% (BRCA2 5%; BRCA1 1%) Gonzalez-Angulo AM, et al. Clin Cancer Res. 2011; Sharma P, et al. Breast Cancer Res Treat. 2014; Rummel S, et al. Breast Cancer Res Treat. 2013; Warner E, et al. J Natl Cancer Inst. 1999; King MC, et al. Science. 2003; Risch HA, et al. J Natl Cancer Inst. 2006; Norquist BM, et al. JAMA Oncol. 2014; Holter S, et al. J Clin Oncol. 2015; Agalliu I, et al. Clin Cancer Res. 2009; Prichard CC, et al. N Engl J Med

13 Management Guidelines for BRCA1/2 Carriers Screening Clinical breast exam Breast MRI Mammogram Management Option Transvaginal US, CA 125 Prevention Bilateral mastectomy Screening Interval/Comment Q6-12 months beginning age 25 Annually: Begin age 25 Annually: Begin age 30 Insufficient data to recommend; may consider starting age Discuss degree of protection, reconstruction options and risks Bilateral salpingo-oophorectomy BRCA1: Age 35-40; BRCA2: By age 45 Consider OCP Consider tamoxifen, raloxifene, or AI NCCN Breast/Ovarian Genetic Assessment Guidelines Version ; Visvanathan K, et al. J Clin Oncol

14 Why Do Genetic Testing of a Cancer Patient? Family members Identify other cancers to screen for/or prevent Treatment Platinum PARP inhibitors

15 PARP Inhibition in Solid Tumors: A Possible Achilles Heel?

16 DNA Damage Response Pathways Base Excision Repair Nucleotide Excision Repair Homologous Repair Non-homologous end-joining Repair Adapted from Chalkiadaki A, Guarente L. Nat Rev Cancer

17 DNA Damage Response Pathways Base Excision Repair Nucleotide Excision Repair Homologous Repair Non-homologous end-joining Repair Adapted from Chalkiadaki A, Guarente L. Nat Rev Cancer

18 PARP Inhibitors: Synthetic Lethality in BRCA Breast Cancers Inglehart JD, Silver DP. N Engl J Med

19 Currently Approved PARP Inhibitors Olaparib Rucaparib Niraparib

20 Olaparib Approved by the US Food and Drug Administration on December 19, 2014, for patients with advanced ovarian cancer. After failing three prior lines of therapy Must have the presence of a germline BRCA 1 or 2 mutation 400 mg twice daily (16 capsules) FDA Prescribing Information.

21 Olaparib Study 19 Randomized phase II, double blind study of recurrent platinum-sensitive serous ovarian cancer Two prior lines of platinum required with complete or partial response to the prior line of platinum 265 women randomized N=136 (olaparib) N=129 (placebo) 136 patients had deleterious BRCA mutation 400 mg twice daily (16 capsules) Ledermann JA, et al. N Engl J Med. 2012; Ledermann JA, et al. Lancet Oncol

22 Probability of Progression- Free Survival PFS in Randomized Population No. at Risk Olaparib Placebo Olaparib 9 Placebo Months since Randomization Hazard ratio, 0.35 (95% CI, ) P< HUGE difference in PFS No. of Patients/ Median Progressionfree Survival (mo) Total No. (%) 60/136 (44.1) /129 (72.1) 4.8 Adapted from Ledermann JA, et al. N Engl J Med

23 Progression-Free Survival (Proportion) Olaparib in Germline BRCA Mutation Tumors Ovarian (median, 7.0 months) Breast (median, 3.7 months) Pancreas (median, 4.6 months) Prostate (median, 7.2 months) Tumor agnostic Median PFS in ovarian cancer: 7 months No. at risk Ovarian Breast Pancreas Prostate Time From First Dose (months) Adapted from Kaufmann B, et al. J Clin Oncol

24 Overall Survival (%) Olaparib in gbrca Overall Survival Olaparib Placebo Deaths/total patients(%) Median OS, months (95% CI) HR 0.62 (95% CI ); P=.025 Olaparib Placebo 47/74 (64%) 48/62 (77%) 34.9 ( ) 30.2 ( ) Germline BRCA mutated N=136 Did not reach pre-specified statistical significance. Number at Risk Olaparib Placebo (0) 69 (4) 65 (0) 56 (2) 50 (0) 39 (0) 33 (0) 27 (0) 27 (0) 27 (0) 25 (0) 23 (0) 11 (11) 1 (9) 0 (1) 62 (0) 58 (2) 52 (1) 40 (0) 34 (1) 29 (0) 25 (0) 20 (0) 19 (0) 15 (0) 13 (1) 10 (0) 6 (3) 0 (6) 0 (0) Adapted from Ledermann JA, et al. Lancet Oncol

25 Rucaparib Approved by the US Food and Drug Administration on December 19, 2016, for patients with advanced ovarian cancer. At least two prior lines of therapy Germline BRCA mutation OR somatic BRCA mutation (tumor specific mutation, methylation or protein loss) 600 mg twice daily (4 tablets) FDA Prescribing Information.

26 Rucaparib ARIEL2 Phase II study of recurrent platinum-sensitive high grade serous ovarian cancer At least one prior platinum therapy 3 pre-specified groups: BRCA mutant (germline or somatic) BRCAwt LOH high BRCAwt LOH low Enrolled N=206 Swisher EM, et al. Lancet Oncol LOH=Loss of Heterozygosity

27 Progression-free Survival Rucaparib in gbrca and BRCAwt PFS BRCA mutant vs. BRCA wild-type and LOH low: HR 0.27 (95% CI ); P<.001 BRCA wild-type and LOH high vs. BRCA wild-type and LOH low: HR 0.62 (95% CI ); P= BRCA mutant BRCA wild-type and LOH high BRCA wild-type and LOH low Number at Risk (number censored) BRCA mutant BRCA wild-type and LOH high BRCA wild-type and LOH low 0 0 Adapted from Swisher EM, et al. Lancet Oncol Time from Start of Treatment (months) 45 (0) 40 (0) 39 (0) 39 (0) 36 (0) 36 (0) 34 (0) 33 (1) 27 (3) 25 (4) 22 (4) 20 (5) 29 (4) 16 (6) 12 (9) 9 (10) 7 (10) 5 (12) 5 (12) 5 (12) 2 (15) 2 (15) 0 (16) 82 (0) 70 (0) 77 (3) 69 (1) 61 (8) 56 (9) 48 (9) 45 (11) 53 (2) 48 (5) 37 (5) 34 (6) 36 (11) 31 (14) 23 (7) 22 (7) 27 (14) 23 (14) 21 (15) 20 (15) 18 (15) 17 (15) 14 (18) 10 (21) 5 (23) 4 (23) 3 (24) 1 (25) 1 (25) 15 (8) 14 (8) 12 (8) 10 (9) 6 (9) 4 (10) 3 (10) 2 (10) 1 (10) 0 (10)

28 Niraparib Approved by the US Food and Drug Administration on March 27, 2017, for recurrent ovarian cancer patients. Maintenance treatment Complete or partial response to platinum chemotherapy 300 mg once daily (3 tablets) FDA Prescribing Information.

29 Niraparib NOVA Randomized, double blind, placebo controlled phase III trial Platinum sensitive epithelial ovarian cancer (majority high grade serous) At least two prior platinum regimens Examination for homologous recombination deficiency (HRD) Randomized 2:1 Enrolled N= gbrca 350 BRCAwt Mirza MR, et al. N Engl J Med

30 Niraparib in gbrca - PFS Mirza MR, et al. N Engl J Med

31 Niraparib in non-gbrca with and without HRD Positivity - PFS No Germline BRCA Mutation with HRD Positivity No Germline BRCA Mutation Mirza MR, et al. N Engl J Med

32 Companion Diagnostics in Ovarian Cancer BRACAnalysis CDx Companion diagnostic (CDx) for olaparib approved by the FDA to identify ovarian cancer with germline BRCA mutations. FoundationFocus CDxBRCA Approved for use with rucaparib Is a next-generation sequencing CDx that detects the presence of deleterious BRCA gene mutations in tumor tissue. mychoice HRD Is being used to predict response to niraparib in clinical trials

33 Managing the Adverse Effects of PARP Inhibitors

34 PARPi Response Rates and Toxicities BRCA1/2 Mutant BRCA1/2 Wild Type and Unknown Drug No. Response No. Response Olaparib Rucaparib >100 (mostly platinum resistant) 39 (all platinum sensitive) 30-60% 46 69% 132 Platinum sensitive 50% Platinum resistant 4% LOH high 29% LOH low 13% Predominant toxicity (in order of frequency) GI symptoms, fatigue, anemia GI symptoms, fatigue, anemia, transient ALT/AST elevations Niraparib 20 (9 platinum sensitive) 40% 3 19 Platinum sensitive 67% Platinum resistant 16% Anemia, thrombocytopenia, neutropenia, GI symptoms, fatigue Talazoparib 26 a 46% - - Fatigue, alopecia, GI symptoms, anemia, neutropenia, thrombocytopenia Veliparib 28 a,b 40% 24 a,b 4% Nausea, fatigue, lymphopenia a Platinum responsiveness not known b Includes triple negative breast cancer Brown JS, et al. Br J Cancer

35 Gastrointestinal Toxicity Nausea Vomiting Constipation Decreased appetite Abdominal pain Diarrhea Dyspepsia FDA Prescribing Information. Toxicity (%) Olaparib Rucaparib Niraparib All Grades Grades 3 & All Grades Grades 3 & All Grades Grades 3 & All Grades Grades 3 & All Grades Grades 3 & All Grades Grades 3 & All Grades Grades 3 & 4 0-0

36 How Do I Manage Adverse Effects Associated with PARP Inhibitors? Nausea/Vomiting Emetogenic potential for PARP inhibitors is moderate risk 1 Frequency of emesis is 30-90% Use PARP inhibitor sooner in disease course. GI symptoms often become more prominent later in disease course. Consider starting PARP inhibitor at lower dose to allow patient to acclimate to drug. Increase dose as tolerated. Prophylactic anti-emetics 30 minutes prior to dosing Encourage small meal prior to dosing Consider dose reduction if not originally started at lower dose Behavioral modifications (avoid carbohydrates, heavy meals) Work on effective bowel regimen 1 NCCN Anti-Emesis Guidelines Version

37 Hematologic Toxicity Decrease in Hgb Decrease in Platelets Decrease in Absolute Neutrophil Count Toxicity (%) Olaparib Rucaparib Niraparib All Grades Grades 3 & All Grades Grades 3 & All Grades Grades 3 & FDA Prescribing Information.

38 How Do I Manage Hematologic Adverse Effects Associated with PARP Inhibitors? Dose Adjustments First Occurrence Second Occurrence Thrombocytopenia Platelets <100,000/µL Withhold treatment of max of 28 days and monitor counts weekly. Resume at same or reduced dose when platelets are 100,000/µL. If platelets were <75,000/µL, resume at reduced dose. Withhold for a max of 28 days and monitor counts weekly. Resume at reduced dose when platelets are 100,000/µL. Neutropenia Neutrophils <1,000/µL Withhold treatment for a max of 28 days and monitor counts weekly. Resume at a reduced dose when neutrophils are 1,500/µL. Discontinue if neutrophils have not returned to acceptable levels after 28 days or if dose has already been reduced to 100 mg/day. Anemia Hgb <8 g/dl Withhold treatment for a max of 28 days and monitor counts weekly. Resume at a reduced dose when Hgb is >9 g/dl. Discontinue if Hgb has not returned to acceptable levels after 28 days or if dose has already been reduced to 100 mg/day. Niraparib FDA Prescribing Information; NCCN Anemia Guidelines Version

39 How Do I Manage Adverse Effects Associated with PARP Inhibitors? Monitor for MDS Check CBC/d prior to starting PARPi (olaparib, rucaparib) and monthly thereafter Check CBC/d weekly x 1 month, then monthly for the next 11 months or longer as indicated (niraparib) If hematological toxicities are noted: Interrupt PARP inhibitor and monitor blood counts weekly until Grade 1 or less If hematological profile recovers, consider restarting drug at a reduced dose If hematological profile has not recovered to Grade 1 or less after 4 weeks, refer to hematologist (bone marrow analysis, cytogenics) Discontinue drug if MDS/AML is confirmed NCCN Anti-Emesis Guidelines Version

40 How Do I Manage Adverse Effects Associated with PARP Inhibitors? Pneumonitis Symptoms include cough, shortness of breath, fatigue and weight loss Discontinue drug Fatigue Monitor for anemia Encourage periods of rest and activity Maintain good nutrition Stay well hydrated Manage stress Consider dose interruption or dose reduction NCCN Cancer-Related Fatigue Guidelines Version ; FDA Prescribing Information;

41 Dose Adjustments for Adverse Effects Olaparib Dose Reductions Dose Starting Dose 400 mg twice daily First Dose Reduction Second Dose Reduction 200 mg twice daily 100 mg twice daily Rucaparib Dose Reductions Starting Dose Dose 600 mg twice daily First Dose Reduction 500 mg twice daily Niraparib Dose Reductions Starting Dose 300 mg daily Dose Second Dose Reduction Third Dose Reduction 400 mg twice daily 300 mg twice daily First Dose Reduction 200 mg daily Second Dose Reduction 100 mg daily FDA Prescribing Information.

42 Other Important Safety Information Females who are able to become pregnant should use birth control during treatment and for six months after last dose. Do not breast feed during treatment and one month (niraparib/olaparib) or two weeks (rucaparib) after last dose. Avoid grapefruit, grapefruit juice and Seville oranges during treatment with olaparib. FDA Prescribing Information.

43 Ensuring Patient Compliance Empower the patient Provide behavioral support Incorporate the medication regimen into daily regimen Adherence aids Medication boxes Patient alarms Patient drug diary Patient communication (telephone calls, scheduled appointments) Manage side effects

44 The Future of PARP Inhibition

45 Future of PARP Inhibitors: Breast Cancer Trial Phase Treatment Arms Inclusion Primary Outcomes OlympiA NCT III Olaparib Placebo gbrca+ DFS OlympiAD NCT III Olaparib Physician s choice chemo gbrca+ PFS ICEBERG NCT II Olaparib BRCA+ ORR BRAVO NCT III Niraparib Physician s choice chemo gbrca+ PFS EMBRACA NCT III Talazoparib Physician s choice chemo gbrca+ PFS BROCADE NCT II Paclitaxel/carboplatin Paclitaxel/carboplatin/veliparib Veliparib/temozolomide gbrca+ PFS

46 Updated Results From OlympiAD June 2017 Trial Phase Treatment Arms Inclusion Primary Outcomes OlympiAD NCT III Olaparib Physician s choice chemo gbrca+ PFS PFS was significantly longer in patients treated with olaparib vs. chemo 7.0 vs. 4.2 months; (HR 0.57; 95% CI: ) P= ORR was 60% in olaparib and 29% in chemo-treated patients Robson ME, et al. ASCO Abstract LBA4.

47 Future of PARP Inhibitors: Pancreatic Cancer Trial Phase Treatment Arms Inclusion Primary Outcomes NCT II Olaparib Non-gBRCA1/2 mutation or HRD deficiency NCT II Olaparib Non-gBRCA1/2 mutation ORR POLO NCT III Olaparib Placebo gbrca1/2 mutation NCT I/II Veliparib/mFOLFOX BRCA1/2 mutation Dose limiting toxicities NCT NCT II II Veliparib Veliparib/gemcitabine/ cisplatin Gemcitabine/cisplatin Veliparib/FOLFIRI FOLFIRI BRCA1/2 or PALB2 mutation Metastatic pancreatic cancer ORR PFS ORR OS

48 Future of PARP Inhibitors: Prostate Cancer Trial Phase Treatment Arms Inclusion PROfound NCT III Olaparib Enzalutamide Abiraterone NCT II Olaparib TRITON3 NCT TRITON2 NCT GALAHAD NCT NCT III II II II Rucaparib Enzalutamide Abiraterone Docetaxel Rucaparib Niraparib Veliparib/abiraterone Abiraterone mcrpc, progression on androgen receptor targeted therapy HRR deficiency in tumor tissue Malignant solid tumor (including prostate) gbrca1/2 mcrpc, progression on androgen receptor targeted therapy BRCA1/2 or ATM mutation mcrpc, progression on 1 androgen receptor targeted therapy and 1 taxane BRCA1/2, ATM or other HR deficiency mcrpc, progression on >1 taxane and >1 androgen receptor targeted therapy Tumor w/ DNA repair anomalies mcrpc, progression on androgen deprivation therapy Primary Outcomes rpfs Tumor response rate rpfs ORR PSA response ORR PSA response

49 Improving Patient Outcomes with PARP Inhibitors: Case-based Treatment Strategies for the Oncology Nurse

50 Case Study 2: DS DS is a 45 year old woman with a BRCA germline mutation and high grade serous adenocarcinoma. December 2013 Underwent a cytoreductive surgery in China. She subsequently received cycle 1 of carboplatin and paclitaxel but developed skin itching and declined further chemotherapy. She was managed with traditional Chinese medicine. May 2014 CT scan revealed recurrent disease. Received carboplatin and docetaxel x 4 cycles. August 2015 Repeat imaging revealed an isolated splenic lesion. She underwent an ex-lap, splenectomy with no residual disease. September 15, 2015 Initiated on single agent carboplatin x 6 given positive washings. November 2016 CA 125 elevated. CT revealed multiple new hepatic lesions. CT guided biopsy of liver mass. December 28, 2016 Initiated on olaparib 400 mg BID

51 Case Study 2: DS December 28, 2016 Initiated on olaparib 400 mg BID January 11, 2017 Patient presented with fatigue, nausea, vomiting, weakness, and abdominal pain Advised patient to hold drug x 7 days Restarted olaparib 400 mg BID Added 8 mg of ondansetron 30 minutes prior to dosing Behavior modifications reviewed Weekly IV hydration January 25, 2017 Patient presented with similar symptoms despite recommendations as above Dose reduced to 300 mg BID

52 Summary Patients with ovarian cancer often have multiple recurrences and many lines of therapy. All patients with ovarian cancer should have BRCA testing and genetic counseling (and certain patients with breast, prostate or pancreatic cancers). Patients with germline and somatic BRCA mutations may benefit from a PARPi with the goal of increased survival. There are three PARPi choices approved for recurrent ovarian cancer, all with separate indications. PARPi s are also being studied in breast, prostate, and pancreatic cancers. PARPi tolerability is achieved with early identification and assessment of hematological adverse effects and proactive prevention of nausea.