Disclaimer • This slide deck in its original and unaltered format is for educational purposes and is current as of May 2017. 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.
Usage Rights • This slide deck is provided for educational purposes and slides may be used for personal, non-commercial presentations only as long as content and references remain the same. • No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts.
Moderator: Paula J. Anastasia RN, MN, AOCN Gyn-Onc Clinical Nurse Specialist Cedars-Sinai Medical Center Los Angeles, CA
Optimizing DNA Damage Response – Targeting Therapies: Focus on Genetic Testing and Counseling Nadine M. Tung, MD Beth Israel Deaconess Medical Center Boston, MA
Genetic Testing and Counseling • Who should get genetic testing? • Which genes should be tested? • How does this impact treatment?
Who Should be Tested for BRCA1/2 Mutations? • 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 2.2017.
Who Should be Tested for BRCA1/2 Mutations? Ovarian Cancer • All EOC/FT/PPC pts • NCCN, ASCO, SGO agree • Insurance cover appropriate pts
NCCN Breast/Ovarian Genetic Assessment Guidelines Version 2.2017; https://www.sgo.org/clinicalpractice/guidelines/genetic-testing-for-ovarian-cancer/; https://www.asco.org/practice-guidelines/practicemanagement-issues/genetics-toolkit/assessing-your-patients-hereditary.
Who Should be Tested for BRCA1/2 Mutations? Breast Cancer • • • • •
≤45 yrs (≤50 yrs if small family/few women) TNBC ≤60 yrs Ashkenazi Jewish ancestry Male Bilateral – 1st ≤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 2.2017.
Who Should be Tested for BRCA1/2 Mutations? Other Cancers • Pancreatic or prostate cancer (Gleason score ≥7): • ≥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 2.2017.
Incidence of BRCA1/2 Germline (Inherited) Mutations • Breast Cancer: • 3-4% (Overall) • 10-20% (TNBC) • 10-15% (Ashkenazi Jewish breast cancer) • Ovarian Cancer: • 15% 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.
Incidence of BRCA1/2 Germline (Inherited) Mutations • Pancreatic Cancer • 1-5% (Overall) • 12% (Ashkenazi Jewish pancreatic cancer) • Prostate Cancer • 1-2% (Overall) • Metastatic: 6% (BRCA2 – 5%; BRCA1 – 1%)
Holter S, et al. J Clin Oncol. 2015; Agalliu I, et al. Clin Cancer Res. 2009; Prichard CC, et al. N Engl J Med. 2016.
BRCA1/2 Repair Double Strand Breaks in DNA: Homologous Recombination
Pennington KP, et al. Gynecol Oncol. 2012.
Criteria for Panel Testing and Types of Panel Testing • No criteria or predictors for mutations in more moderate risk genes • Multi-gene panels • High risk genes (>5x risk cancer) vs. high and moderate risk (2-5x risk cancer) • By cancer type or all cancers
Tung N, et al. Nat Rev Clin Oncol. 2016.
Breast/Ovarian Cancer Risks with Novel Genes Gene
Breast
Ovary
PALB2 ATM CHEK2 (truncating) NBN NF1 BRIP1 RAD51C RAD51D
Y (RR 5.3) Y (RR 2.8) Y (RR 3.0) Y (RR 2.7) Y (RR 2.6)
? (RR 2.3-10.2)
Y (RR 3.4-11.2) Y (OR 5.2) Y (OR 12)
Easton DF, et al. N Engl J Med. 2015; Antoniou AC, et al. N Engl J Med. 2014; Norquist BM, et al. JAMA Oncol. 2015; Ramus SJ, et al. J Natl Cancer Inst. 2015; Song H, et al. J Clin Oncol. 2015.
Risk of Breast Cancer Associated with Inherited Mutations Gene High Penetrance BRCA1 BRCA2 PALB2 Moderate Penetrance ATM CHEK2
Breast Cancer Risk (by age 70) 57-87% 57-87% 33-58% 20-30% 20-30%
Antoniou AC, et al. N Engl J Med. 2014; Tung N, et al. Nat Rev Clin Oncol. 2016; Graffeo R, et al. Breast Cancer Res Treat. 2016.
Management Guidelines for BRCA1/2 Carriers Management Option
Screening Interval/Comment
Screening • Clinical breast exam • Breast MRI • Mammogram • Transvaginal US, CA 125
• • • •
Q6-12 months beginning age 25 Annually: Begin age 25 Annually: Begin age 30 Insufficient data to recommend; may consider starting age 30-35
Prevention • Bilateral mastectomy
• 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 2.2017; Visvanathan K, et al. J Clin Oncol. 2013.
NCCN Guidelines Version 2.2017 Breast/Ovarian Management Based on Genetic Test Results Gene
Intervention warranted based on gene and/or risk level
Recommended Breast MRI (>20% risk of breast cancer) ATM BRCA1 BRCA2 CDH1 CHEK2 NBN NF1 PALB2 PTEN TP53
NCCN Breast/Ovarian Genetic Assessment Guidelines Version 2.2017.
Discuss Option of RRM BRCA1 BRCA2 CDH1 PTEN TP53 PALB2*
*Consider based on family history
Risk of Ovarian Cancer Gene BRCA1 BRCA2 BRIP1 RAD51C RAD51D PALB2
Estimated Lifetime Recommended Age for RRSO Risk of Ovarian Cancer 31-59% 18-34%
35-40 By age 45
13% (or lower?) 6% 14%
>45 >45 >45
2.6-11% ??
Unknown or insufficient evidence
NCCN Breast/Ovarian Genetic Assessment Guidelines Version 2.2017; Hartmann LC, et al. N Engl J Med. 2016; Antoniou AC, et al. N Engl J Med. 2014; Norquist BM, et al. JAMA Oncol. 2015; Ramus SJ, et al. J Natl Cancer Inst. 2015; Song H, et al. J Clin Oncol. 2015; Chen S. Parmigiani G. J Clin Oncol. 2007; Mavaddat N, et al. J Natl Cancer Inst. 2013.
Why Do Genetic Testing of a Cancer Patient? • Family members • Identify other cancers to screen for/or prevent • Treatment • Platinum • PARP inhibitors
The Development of Hereditary Cancer
1 damaged gene 1 normal gene All cells in the body: One functioning BRCA gene
2 damaged genes Cancer cells: No functioning BRCA gene
Tumor Develops
Platinum Damage
Evans MK, Longo DL. N Engl J Med. 2014.
DS DNA Break
Platinum is Effective in Cancers in Patients with BRCA1/2 Mutations • Platinum causes more DS DNA breaks • Cancers without BRCA1 or BRCA2 can’t repair these breaks • Ovarian cancer patients with BRCA1/2 mutations have a better prognosis • In part due to higher sensitivity to platinum • BRCA1/2 breast cancer • Platinum is effective but less data (most info is for TNBC) • Still being studied Evans MK, Longo DL. N Engl J Med. 2014; https://www.asco.org/practice-guidelines/cancer-care-initiatives/genetics-toolkit/genetic-testing.
Why Do Genetic Testing of a Cancer Patient? • Family members • Identify other cancers to screen for or prevent • Treatment • Platinum • PARP inhibitors
Platinum Damage
Evans MK, Longo DL. N Engl J Med. 2014.
SS DNA Break
DS DNA Break
PARP Inhibitors: Synthetic Lethality in BRCA Breast Cancers
Inglehart JD, Silver DP. N Engl J Med. 2009.
PARP Inhibition: A Possible Achilles Heel for Solid Tumors? BJ Rimel, MD Cedars-Sinai Medical Center Los Angeles, CA
What is PARP? • Poly (ADP-Ribose) Polymerase Single Strand Break
PARP Unrepaired double Doublebreaks Strand Break strand lead from radiation or to CELL DEATH!!! chemotherapy
Morales J, et al. Crit Rev Eukaryot Gene Expr. 2014.
DNA
AZ1775
Inactive
Olaparib Mitosis
Active
Rationale for PARP inhibition: antiangiogenesis and cell cycle inhibition Cediranib
Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci. 2016.
DNA
AZ1775
Inactive
Olaparib Mitosis
Active
Rationale for PARP inhibition: antiangiogenesis and cell cycle inhibition Cediranib
Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci. 2016.
DNA
AZ1775
Inactive
Olaparib Mitosis
Active
Rationale for PARP inhibition: antiangiogenesis and cell cycle inhibition Cediranib
Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci. 2016.
DNA
AZ1775
Inactive
Olaparib Mitosis
Active
Rationale for PARP inhibition: antiangiogenesis and cell cycle inhibition Cediranib
Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci. 2016.
Currently Approved PARP Inhibitors • Olaparib • Rucaparib • Niraparib
PARP Inhibitors in Clinical Trials • Veliparib • Talazoparib
www.clinicaltrials.gov.
Olaparib • On December 19, 2014, the US Food and Drug Administration (FDA) approved olaparib capsules as monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA mutated (gBRCAm) (as detected by an FDAapproved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. • Concurrent with this action, FDA approved a multiplex PCR companion diagnostic test for the qualitative detection and classification of variants in the BRCA1 and BRCA2 genes. FDA Prescribing Information; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P140020.
Olaparib Indication • Olaparib is approved for women with a germline BRCA mutation • After failing three prior lines of therapy for ovarian cancer • Has a companion diagnostic test, which is a blood test for the presence of a germline BRCA 1 or 2 mutation
• 400 mg twice daily (16 capsules)
FDA Prescribing Information.
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. 2014.
Probability of ProgressionFree Survival
PFS in Randomized Population 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Hazard ratio, 0.35 (95% CI, 0.25-0.49) P<.001
HUGE difference in PFS
Olaparib No. of Patients/ Total No. (%) 60/136 (44.1) 93/129 (72.1)
Placebo 0
No. at Risk 136 Olaparib Placebo 129
3 6 9 12 Months since Randomization
104 72
51 23
23 7
Adapted from Ledermann JA, et al. N Engl J Med. 2012.
6 1
15 0 0
Median Progressionfree Survival (mo) 8.4 4.8
Subgroup Analysis of PFS in Randomized Population
Ledermann JA, et al. N Engl J Med. 2012.
Olaparib in Germline BRCA Mutation Tumors Progression-Free Survival (Proportion)
0.8
0.6 0.4 0.2
0 No. at risk Ovarian Breast Pancreas Prostate
• Germline BRCA mutation carriers • Tumor agnostic • Median PFS in ovarian cancer: 7 months
Ovarian (median, 7.0 months) Breast (median, 3.7 months) Pancreas (median, 4.6 months) Prostate (median, 7.2 months)
1.0
193 62 23 8
3
6
131 32 13 6
85 15 8 5
15 9 12 18 21 Time From First Dose (months) 29 56 16 10 4 9 5 3 2 2 3 1 1 1 0 2 2 2 0 0
Adapted from Kaufmann B, et al. J Clin Oncol. 2015.
24
27
2 1 0 0
0 0 0 0
Overall Survival (%)
Olaparib in gBRCA and BRCAwt Overall Survival 100 90 80 70 60 50 40 30 20 10 0
0 Number at Risk Olaparib 136 (0) Placebo 129 (0)
Deaths/total patients (%) Median OS, months (95% CI)
Olaparib
Placebo
94/136 (69%) 29.8 (26.9-35.7)
109/129 (84%) 27.8 (24.9-33.7)
HR 0.73 (95% CI 0.55-0.96); P=.025 All patients randomized (N=265) Did not reach pre-specified statistical significance. Olaparib Placebo 6
12
18
24
30
36
42
48
54
60
66
72
78
84
129 (5) 122 (3)
117 (2) 112 (1)
97 (2) 90 (0)
79 (0) 75 (1)
62 (0) 57 (0)
52 (0) 44 (0)
43 (0) 37 (0)
42 (0) 32 (0)
41 (0) 27 (0)
37 (0) 24 (1)
35 15 (0) (19) 18 9 (0) (5)
2 (12) 1 (8)
0 (2) 0 (1)
Adapted from Ledermann JA, et al. Lancet Oncol. 2016.
Overall Survival (%)
Olaparib in gBRCA – Overall Survival 100 90 80 70 60 50 40 30 20 10 0
0 Number at Risk Olaparib 74 (0) Placebo 62 (0)
Deaths/total patients(%) Median OS, months (95% CI)
Olaparib
Placebo
47/74 (64%) 34.9 (29.2-54.6)
48/62 (77%) 30.2 (23.1-40.7)
HR 0.62 (95% CI 0.41-0.94); P=.025 Germline BRCA mutated N=136 Did not reach pre-specified statistical significance. Olaparib Placebo 6
12
18
24
30
36
42
48
54
60
66
72
78
84
69 (4) 58 (2)
65 (0) 52 (1)
56 (2) 40 (0)
50 (0) 34 (1)
39 (0) 29 (0)
33 (0) 25 (0)
27 (0) 20 (0)
27 (0) 19 (0)
27 (0) 15 (0)
25 (0) 13 (1)
23 11 (0) (11) 10 6 (0) (3)
1 (9) 0 (6)
0 (1) 0 (0)
Adapted from Ledermann JA, et al. Lancet Oncol. 2016.
Rucaparib • On December 19, 2016, the US Food and Drug Administration granted accelerated approval to rucaparib for treatment of patients with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer who have been treated with two or more chemotherapies. • Concurrent with this action, the FDA approved a next generation sequencing-based companion diagnostic test for use with rucaparib to detect the presence of deleterious mutations.
https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm533873.htm.
Rucaparib Indication • 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.
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. 2017.
Rucaparib in gBRCA and BRCAwt – PFS 100
BRCA mutant vs. BRCA wild-type and LOH low: HR 0.27 (95% CI 0.16-0.44); P<.001 BRCA wild-type and LOH high vs. BRCA wild-type and LOH low: HR 0.62 (95% CI 0.42-0.90); P=.011
90
Progression-free Survival
80 70 60 50 40 30
BRCA mutant BRCA wild-type and LOH high BRCA wild-type and LOH low
20 10 0 Number at Risk
0
1
2
3
4
(number censored)
5
6
7
8
9
10
11
12
13
14
Time from Start of Treatment (months)
15
16
17
18
19
20
BRCA mutant 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) BRCA wild-type and LOH high 82 (0) 77 (3) 61 (8) 56 (9) 48 (9) 45 (11) 36 (11) 31 (14) 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) BRCA wild-type and LOH low 70 (0) 69 (1) 53 (2) 48 (5) 37 (5) 34 (6) 23 (7) 22 (7) 15 (8) 14 (8) 12 (8) 10 (9) 6 (9) 4 (10) 3 (10) 2 (10) 1 (10) 0 (10)
Adapted from Swisher EM, et al. Lancet Oncol. 2017.
21
Niraparib • On March 27, 2017, the US Food and Drug Administration approved niraparib, a poly ADP-ribose polymerase (PARP) inhibitor, for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm548487.htm.
Niraparib Indication • Maintenance treatment • Recurrent ovarian cancer
• Complete or partial response to platinum chemotherapy • 300 mg once daily (3 tablets)
FDA Prescribing Information.
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=553 • 203 gBRCA • 350 BRCAwt Mirza MR, et al. N Engl J Med. 2016.
Niraparib in gBRCA – PFS
Mirza MR, et al. N Engl J Med. 2016.
Niraparib in non-gBRCA with and without HRD Positivity – PFS No Germline BRCA Mutation with HRD Positivity
Mirza MR, et al. N Engl J Med. 2016.
No Germline BRCA Mutation
Selected Toxicity ≥Grade 3 Nausea Vomiting Constipation Anemia Olaparib1 Rucaparib2 Niraparib3
1Kaufmann
0.5% 4% 3%
2.6% 2% 1.9%
<5% 1% 0.5%
18.7% 21% 25.3%
Thrombocytopenia <5% 2% 33.8%
B, et al. J Clin Oncol. 2015; 2Swisher EM, et al. Lancet Oncol. 2017; 3Mirza MR, et al. N Engl J Med. 2016.
Fatigue 6.2% 9% 8.2%
PARPi Response Rates and Toxicities BRCA1/2 Mutant
BRCA1/2 Wild Type and Unknown
Drug
No.
Response
No.
Response
Predominant toxicity (in order of frequency)
Olaparib
>100 (mostly platinum resistant)
30-60%
46
Platinum sensitive 50% Platinum resistant 4%
GI symptoms, fatigue, anemia
Rucaparib
39 (all platinum sensitive)
69%
132
LOHhigh 29% LOHlow 13%
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
26a
46%
-
-
Fatigue, alopecia, GI symptoms, anemia, neutropenia, thrombocytopenia
Veliparib
28a,b
40%
24a,b
4%
Nausea, fatigue, lymphopenia
aPlatinum
responsiveness not known bIncludes triple negative breast cancer
Brown JS, et al. Br J Cancer. 2016.
PARP Inhibitors in BRCA+ Breast Cancer Nadine M. Tung, MD Beth Israel Deaconess Medical Center Boston, MA
PARP Inhibitors: Women with gBRCA+ Breast Cancer (Iceberg Trial: Olaparib) • 27 metastatic BRCA+ breast cancer at 400 mg twice daily • Many patients heavily pre-treated • 41% RR • 85% responded or had stable disease • Responses seen in ER+ and ER-neg (TNBC) • Well tolerated, oral therapy Tutt A, et al. Lancet. 2010; Audeh MW, et al. Lancet. 2010.
Randomized PARP Inhibitor Studies in Metastatic Breast Cancer: BRCA1/2 PARP inhibitor daily gBRCA+ metastatic disease
Randomized Anthracycline, taxane resistant
BRAVO Trial (NCT01905592) - Niraparib EMBRACA (NCT01945775) - Talazoparib OLYMPIAD Trial (NCT02000622) - Olaparib
Standard Chemo, MD’s choice:
Capecitabine or Vinorelbine or Eribulin or Gemcitabine
Primary Endpoint: PFS
Randomized PARP Inhibitor Studies in Metastatic Breast Cancer: BRCA1/2 PARP inhibitor daily gBRCA+ metastatic disease
OlympiAD Trial: Randomized
Anthracycline, taxane resistant
Chemo, MD’s “Positive”: IncreasedStandard PFS for olaparib vs choice: chemotherapy Capecitabine or Vinorelbine or Results: ASCO 2017 Eribulin or
BRAVO Trial (NCT01905592) - Niraparib EMBRACA (NCT01945775) – Talazoparib OLYMPIAD Trial (NCT02000622) - Olaparib
Gemcitabine
https://www.astrazeneca.com/media-centre/press-releases/2017/lynparza-meets-primary-endpoint-in-phase-iii-trial-in-brca-mutatedmetastatic-breast-cancer-17022017.html
Primary Endpoint: PFS
Olaparib in Adjuvant Breast Cancer Setting: OlympiA PARP inhibitor daily X 1 yr
gBRCA+ TNBC or ER+ I. Adjuvant: T2 or N+ II. Neoadjuvant: Residual disease
www.clinicaltrials.gov; NCT02032823.
Randomized After chemo and surgery
Placebo X 1 yr
Endpoints: DFS DDFS OS
Efficacy of PARP Inhibitors may be Lower in Breast Cancer pts with Prior Platinum • Study 42: Study of various gBRCA+ cancers • 62 breast cancer pts • ≥3 prior chemo in metastatic setting • ORR 12.9% • Response rate differed if prior platinum (20% vs. 9.5%) Kaufman B, et al. J Clin Oncol. 2015.
Reversion Mutations • …have been described in BRCA+ breast cancers after platinum • The new mutation restores the BRCA1 or BRCA2 function in the cancer cell • So PARP inhibitor may not work
Afghahi A, et al. Clin Cancer Res. 2017.
Select Studies Combining PARPi with Platinum Chemotherapy • BROCADE (NCT01506609) • Paclitaxel/carboplatin vs. paclitaxel/carboplatin/veliparib vs. veliparib/temozolomide • gBRCA+ metastatic breast cancer • Study 211 (NCT00782574) • Cisplatin/olaparib • Advanced solid tumors • Carboplatin/olaparib2 (NCT01445418) • BRCA+ advanced breast, ovarian cancer 1Balmaña
J, et al. Ann Oncol. 2014; 2Lee JM, et al. J Natl Cancer Inst. 2014.
Hard to Combine Chemo and PARPi • Myelosuppression – limit dose chemo and PARPi
PARP Inhibitors in Additional Solid Tumors
Ongoing PARPi Trials in Pancreatic Cancer Trial
Phase
NCT02511223
II
• Olaparib
NCT02677038
II
• Olaparib
• Non-gBRCA1/2 mutation
ORR
POLO NCT02184195
III
• Olaparib • Placebo
• gBRCA1/2 mutation
PFS
NCT01489865
I/II
• Veliparib/mFOLFOX
• BRCA1/2 mutation
Dose limiting toxicities
NCT01585805
II
NCT02890355
II
www.clinicaltrials.gov.
Treatment Arms
Inclusion • Non-gBRCA1/2 mutation or HRD deficiency
• Veliparib • Veliparib/gemcitabine/ • BRCA1/2 or PALB2 mutation cisplatin • Gemcitabine/cisplatin • Veliparib/FOLFIRI • Metastatic pancreatic cancer • FOLFIRI
Primary Outcomes ORR
ORR
OS
FOLFIRI: Fluorouracil, irinotecan, leucovorin; mFOLFOX: Modified 5-fluorouracil and oxaplatin
Ongoing PARPi Trials in Prostate Cancer Trial PROfound NCT02987543
NCT01078662 TRITON3 NCT02975934 TRITON2 NCT02952534
Phase
Treatment Arms
Inclusion
III
• Olaparib • Enzalutamide • Abiraterone
• mCRPC, progression on androgen receptor targeted therapy • HRR deficiency in tumor tissue
II
• Olaparib
• Malignant solid tumor (including prostate) • gBRCA1/2
III
• Rucaparib • Enzalutamide • Abiraterone • Docetaxel
• mCRPC, progression on androgen receptor targeted therapy • BRCA1/2 or ATM mutation
• Rucaparib
• mCRPC, progression on 1 androgen receptor targeted therapy and 1 taxane • BRCA1/2, ATM or other HR deficiency
II
GALAHAD NCT02854436
II
• Niraparib
• mCRPC, progression on >1 taxane and >1 androgen receptor targeted therapy • Tumor w/ DNA repair anomalies
NCT01576172
II
• Veliparib/abiraterone • Abiraterone
• mCRPC, progression on androgen deprivation therapy
www.clinicaltrials.gov.
Primary Outcomes rPFS Tumor response rate rPFS
ORR PSA response ORR PSA response
Improving Patient Outcomes with PARP Inhibitors: Case-based Treatment Strategies for the Oncology Nurse Lisa Arvine, RN, MSN, ANP-BC, WHNP-BC Dana-Farber Cancer Institute Boston, MA
Overview • Procuring PARP inhibitors for patients
• Understand adverse events associated with PARP inhibitors • Dosing of PARP inhibitors
• How to manage adverse effects and discuss ways the oncology nurse can optimize therapy • Understand ways nurses can improve adherence to PARP inhibitors • Patient based cases
How Do I Procure PARP Inhibitors for My Patients? Rucaparib • FDA approved for patients with advanced ovarian cancer who have BRCA gene mutations, either inherited (germline) or acquired (somatic) • Two or more prior lines of chemotherapy • Next generation sequencing-based companion diagnostic approved to test for deleterious mutations
Olaparib • FDA approved for patients with advanced ovarian cancer who have BRCA gene mutation (germline) • Three or more prior lines of chemotherapy
• Multiplex PCR companion diagnostic approved to detect germline mutation Niraparib • Maintenance treatment in recurrent ovarian, fallopian or primary peritoneal who have had a complete or partial response to platinum based therapy FDA Prescribing Information.
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
Mutation only found in tumor
Unaffected children
Inheritable
Mutation in egg or sperm
Adapted from https://www.cancer.org/cancer/cancer-causes/genetics/family-cancer-syndromes.html.
All cells affected in children
Common Adverse Effects of PARP Inhibitors • Fatigue
• Changes in kidney function tests
• Nausea and/or vomiting
• Shortness of breath
• Decreased appetite
• Anemia
• Dysgeusia
• Arthralgias/mylagias
• Abdominal pain
• Rash
• Myelosuppression
• Myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia (AML)*
FDA Prescribing Information.
*Although rare, can be delayed and life threatening
Drug Specific Adverse Effects Rucaparib • Constipation and/or diarrhea • Changes in liver function tests • Increased cholesterol levels
FDA Prescribing Information.
Olaparib • Indigestion/heartburn • Rhinorrhea • Pneumonitis
Niraparib • Palpitations • Mucositis/dry mouth • Increase in AST/ALT • Urinary tract infections • Hypertension • Headache/dizziness
Dosing • Rucaparib 600 mg (two 300 mg tablets) taken orally twice daily • Rucaparib is available in 300 mg and 200 mg tablets • Olaparib 400 mg (eight 50 mg capsules) taken orally twice daily • Niraparib 300 mg (three 100 mg capsules) taken once daily
FDA Prescribing Information.
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.
How Do I Manage Hematologic Adverse Effects Associated with PARP Inhibitors? •Prior to initiating PARP inhibitor, prior chemotherapy adverse effects should have resolved to 100,000/µL. Resume at same or reduced dose •Second occurrence: Hold until platelets >100,000/µL. Resume at reduced dose •Discontinue if platelets have not returned to acceptable levels after 28 days •Transfuse as needed •Monitor closely for MDS FDA Prescribing Information; NCCN Anemia Guidelines Version 2.2017.
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 and 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 FDA Prescribing Information.
How Do I Manage Adverse Effects Associated with PARP Inhibitors? Nausea/Vomiting • 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 antiemetics 30 minutes prior to dosing • Encourage small meal prior to dosing • Consider dose reduction if not originally started at lower dose • Try behavioral modifications GI Toxicity • Small frequent meals • Behavioral modifications (avoid carbohydrates, heavy meals) • Work on effective bowel regimen
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 FDA Prescribing Information; NCCN Cancer-Related Fatigue Guidelines Version 1.2017; https://radiopaedia.org/articles/hypersensitivity-pneumonitis.
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
Case Study 1: JG Ms. JG is a 65 year old woman with a BRCA germline mutation. 2002 • Diagnosed with a stage IIA papillary serous ovarian cancer. Underwent cytoreductive surgery followed by adjuvant carboplatin and paclitaxel x 6 cycles. December 2013 • Diagnosed with recurrent disease. Underwent a secondary cytoreductive surgery followed by adjuvant carboplatin and gemcitabine x 6 cycles. Completed May 2014. July 2014 • Enrolled in the SOLO2 trial evaluating olaparib 300 mg BID as maintenance therapy.
Case Study 1: JG August 26, 2014 • Presented with Grade 3 anemia (Hct of 18) with low reticulocyte count. Leukopenia noted. Platelets normal. • Olaparib interrupted • 2 units of PRBC given • Rule out other sources of anemia: • Iron studies ordered • Guaiac test done • Hemolysis panel August 29, 2014 • Repeat labs revealed anemia improved to Grade 2. • Referred to Hematology to rule out aplastic anemia. Per Hematology, anemia related to olaparib.
Case Study 1: JG September 5, 2014 • Patient presented with Grade 2 fatigue and Grade 1 anemia. • Continued to hold olaparib September 23, 2014 • Olaparib restarted at 300 mg BID • CBC/d weekly October 16, 2014 • Patient presented with Grade 2 fatigue and Grade 2 anemia (Hct 26.5). • Olaparib discontinued given concern for potential MDS. November 2016 • Rising CA 125, CT with recurrent disease
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
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 3 days • Restarted olaparib 400 mg BID • Added prochlorperazine 10 mg 30 minutes prior to dosing • Behavior modifications reviewed January 25, 2017 • Patient presented with similar symptoms despite recommendations as above • Dose reduced to 300 mg BID
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.