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• This slide deck in its original and unaltered format is for educationalpurposes and is current as of May 2017. The content and viewspresented in this educational activity are those of the authors and donot necessarily reflect those of Creative Educational Concepts or thesupporter.
• These materials may discuss therapeutic products that have not beenapproved by the US Food and Drug Administration and off-label usesof approved products. A qualified healthcare professional should beconsulted before using any therapeutic product discussed. Readersshould verify all information and data before treating patients oremploying any therapies described in this educational activity.
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Usage Rights
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, MDBeth Israel Deaconess Medical Center
Boston, MA
•Who should get genetic testing?
•Which genes should be tested?
•How does this impact treatment?
Genetic Testing and Counseling
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/clinical-practice/guidelines/genetic-testing-for-ovarian-cancer/; https://www.asco.org/practice-guidelines/practice-management-issues/genetics-toolkit/assessing-your-patients-hereditary.
• ≤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? Breast Cancer
• 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.
Who Should be Tested for BRCA1/2 Mutations? Other Cancers
• 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.
Incidence of BRCA1/2 Germline (Inherited) Mutations
Pennington KP, et al. Gynecol Oncol. 2012.
BRCA1/2 Repair Double Strand Breaks in DNA: Homologous Recombination
• 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
Criteria for Panel Testing and Types of Panel Testing
Tung N, et al. Nat Rev Clin Oncol. 2016.
Gene Breast Ovary
PALB2 Y (RR 5.3) ? (RR 2.3-10.2)
ATM Y (RR 2.8)
CHEK2 (truncating) Y (RR 3.0)
NBN Y (RR 2.7)
NF1 Y (RR 2.6)
BRIP1 Y (RR 3.4-11.2)
RAD51C Y (OR 5.2)
RAD51D 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.
Breast/Ovarian Cancer Risks with Novel Genes
Gene Breast Cancer Risk (by age 70)
High Penetrance
BRCA1 57-87%
BRCA2 57-87%
PALB2 33-58%
Moderate Penetrance
ATM 20-30%
CHEK2 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.
Risk of Breast Cancer Associated with Inherited Mutations
Management Guidelines for BRCA1/2 Carriers
Management Option Screening Interval/Comment
Screening
• Clinical breast exam• Breast MRI• Mammogram
• Q6-12 months beginning age 25• Annually: Begin age 25• Annually: Begin age 30
• Transvaginal US, CA 125• 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.
GeneRecommended Breast MRI(>20% risk of breast cancer)
Discuss Option of RRM
Intervention warranted based on
gene and/or risk level
ATMBRCA1BRCA2CDH1CHEK2NBNNF1
PALB2PTENTP53
BRCA1BRCA2CDH1PTENTP53
PALB2*
NCCN Breast/Ovarian Genetic Assessment Guidelines Version 2.2017.
NCCN Guidelines Version 2.2017 Breast/Ovarian Management Based on Genetic Test Results
*Consider based on family history
GeneEstimated Lifetime
Risk of Ovarian Cancer Recommended Age for RRSO
BRCA1 31-59% 35-40
BRCA2 18-34% By age 45
BRIP1 13% (or lower?) >45
RAD51C 6% >45
RAD51D 14% >45
PALB2 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.
Risk of Ovarian Cancer
• Family members
• Identify other cancers to screen for/or prevent
• Treatment• Platinum
• PARP inhibitors
Why Do Genetic Testing of a Cancer Patient?
1 damaged gene1 normal gene
The Development of Hereditary Cancer
All cells in the body: One functioning BRCA gene
2 damaged genes
Cancer cells: No functioning BRCA gene
Tumor Develops
Evans MK, Longo DL. N Engl J Med. 2014.
Platinum Damage DS DNA Break
• 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.
Platinum is Effective in Cancers in Patients with BRCA1/2 Mutations
• Family members
• Identify other cancers to screen for or prevent
• Treatment• Platinum
• PARP inhibitors
Why Do Genetic Testing of a Cancer Patient?
Evans MK, Longo DL. N Engl J Med. 2014.
Platinum Damage DS DNA BreakSS DNA Break
Inglehart JD, Silver DP. N Engl J Med. 2009.
PARP Inhibitors: Synthetic Lethality in BRCABreast Cancers
PARP Inhibition: A Possible Achilles Heel for Solid Tumors?
BJ Rimel, MDCedars-Sinai Medical Center
Los Angeles, CA
• Poly (ADP-Ribose) PolymeraseSingle Strand Break
Double Strand Break from radiation or chemotherapy
Morales J, et al. Crit Rev Eukaryot Gene Expr. 2014.
PARP
What is PARP?
Unrepaired double strand breaks lead to CELL DEATH!!!
Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci. 2016.
Cediranib
Olaparib
Rationale for PARP inhibition: antiangiogenesis
and cell cycle inhibition
AZ1775DNA
Mitosis
Active
Inactive
Cediranib
Olaparib
AZ1775DNA
Mitosis
Active
Inactive
Rationale for PARP inhibition: antiangiogenesis
and cell cycle inhibition
Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci. 2016.
Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci. 2016.
Cediranib
Olaparib
Rationale for PARP inhibition: antiangiogenesis
and cell cycle inhibition
AZ1775DNA
Mitosis
Active
Inactive
Ivy SP, et al. Expert Opin Investig Drugs. 2016; Matheson CJ, et al. Trends Pharmacol Sci. 2016.
Cediranib
Olaparib
Rationale for PARP inhibition: antiangiogenesis
and cell cycle inhibition
AZ1775DNA
Mitosis
Active
Inactive
•Olaparib
•Rucaparib
•Niraparib
Currently Approved PARP Inhibitors
PARP Inhibitors in Clinical Trials
•Veliparib
• Talazoparib
www.clinicaltrials.gov.
• 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 FDA-approved 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
• Olaparib is approved for women with a germline BRCAmutation
• 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 Indication
• 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.
Olaparib
HUGE difference in PFS
Adapted from Ledermann JA, et al. N Engl J Med. 2012.
No. of Patients/ Total No. (%)
60/136 (44.1)
93/129 (72.1) 4.8
8.4
Median Progression-free Survival (mo)
Olaparib
Placebo
151296300.00.10.20.30.40.50.60.70.80.91.0
Pro
bab
ility
of
Pro
gre
ssio
n-
Fre
e S
urv
ival
Months since RandomizationNo. at RiskOlaparibPlacebo
136
129 72104
2351 23
761
00
Hazard ratio, 0.35 (95% CI, 0.25-0.49)P<.001
PFS in Randomized Population
Subgroup Analysis of PFS in Randomized Population
Ledermann JA, et al. N Engl J Med. 2012.
• Germline BRCA mutation carriers
• Tumor agnostic
• Median PFS in ovarian cancer: 7 months
Adapted from Kaufmann B, et al. J Clin Oncol. 2015.
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)
1.0
0.8
0.6
0.4
0.2
0 3 6 9 12 15 18 21 24 27
Time From First Dose (months)No. at risk
Ovarian
Breast
Pancreas
Prostate
193 131
6223
8 6 5 2 2 2 0
3213
85
15
56 29 16 10
9 5 3 2 28 3 1 1 1
0
0
0
0
0
00
02
1
4
Pro
gre
ssio
n-F
ree
Su
rviv
al
(Pro
po
rtio
n)
Adapted from Ledermann JA, et al. Lancet Oncol. 2016.
All patients randomized (N=265)Did not reach pre-specified statistical significance.
Olaparib Placebo
Deaths/total patients (%)Median OS, months (95% CI)
HR 0.73 (95% CI 0.55-0.96); P=.025
94/136 (69%) 109/129 (84%)29.8 (26.9-35.7) 27.8 (24.9-33.7)
(8) (1)(0)(0) (1) (5)(0) (0) (0) (0)(1)(0)(0) (3) (1)
426 12 18 30 54 60
100
90
80
70
60
50
40
30
20
10
00 24 36 48 66 72 78 84
Number at RiskOlaparib
Placebo
136 129 117 97 79 62 52 43 42 41 37 35 15 2 0
01129 122 112 90 75 57 44 37 32 27 24 18 9
(0) (0) (0) (19) (12) (2)(0) (0) (0)(0)(0)(0) (2)(5) (2)
Ove
rall
Surv
ival
(%
)
Olaparib in gBRCA and BRCAwtOverall Survival
Olaparib
Placebo
Adapted from Ledermann JA, et al. Lancet Oncol. 2016.
Germline BRCA mutated N=136Did not reach pre-specified statistical significance.
Olaparib Placebo
Deaths/total patients(%)Median OS, months (95% CI)
HR 0.62 (95% CI 0.41-0.94); P=.025
47/74 (64%) 48/62 (77%)34.9 (29.2-54.6) 30.2 (23.1-40.7)
(6) (0)(0)(0) (1) (3)(0) (0) (0) (0)(1)(0)(0) (2) (1)
426 12 18 30 54 60
100
90
80
70
60
50
40
30
20
10
00 24 36 48 66 72 78 84
Number at RiskOlaparib
Placebo
74 69 65 56 50 39 33 27 27 27 25 23 11 1 0
0062 58 52 40 34 29 25 20 19 15 13 10 6
(0) (0) (0) (11) (9) (1)(0) (0) (0)(0)(0)(0) (0)(4) (2)
Ove
rall
Surv
ival
(%
)Olaparib in gBRCA – Overall Survival
Olaparib
Placebo
• 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 rucaparibto detect the presence of deleterious mutations.
https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm533873.htm.
Rucaparib
• 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 Indication
• 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
Adapted from Swisher EM, et al. Lancet Oncol. 2017.
BRCA mutantBRCA wild-type and LOH highBRCA wild-type and LOH low
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
21201918171615141312111098765432100
100
90
80
70
60
50
40
30
20
10
Pro
gre
ssio
n-f
ree
Su
rviv
al
Time from Start of Treatment (months)Number at Risk(number censored)
BRCA mutant
BRCA wild-type and LOH high
BRCA wild-type and LOH low
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)
48 (5)53 (2) 37 (5) 34 (6)
45 (11)23 (7)36 (11) 31 (14)
22 (7)27 (14) 23 (14)
15 (8) 14 (8) 12 (8)
21 (15) 20 (15) 18 (15)
10 (9) 6 (9) 4 (10)
17 (15) 14 (18)
3 (10) 2 (10) 1 (10) 0 (10)
10 (21) 5 (23) 4 (23) 3 (24) 1 (25) 1 (25)
Rucaparib in gBRCA and BRCAwt – PFS
• 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
• Maintenance treatment
• Recurrent ovarian cancer
• Complete or partial response to platinum chemotherapy
• 300 mg once daily (3 tablets)
FDA Prescribing Information.
Niraparib Indication
• 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 BRCAwtMirza MR, et al. N Engl J Med. 2016.
Niraparib
Mirza MR, et al. N Engl J Med. 2016.
Niraparib in gBRCA – PFS
Mirza MR, et al. N Engl J Med. 2016.
No Germline BRCA Mutation with HRD Positivity No Germline BRCA Mutation
Niraparib in non-gBRCA with and without HRD Positivity – PFS
Nausea Vomiting Constipation AnemiaThrombo-cytopenia
Fatigue
Olaparib1 0.5% 2.6% <5% 18.7% <5% 6.2%
Rucaparib2 4% 2% 1% 21% 2% 9%
Niraparib3 3% 1.9% 0.5% 25.3% 33.8% 8.2%
1Kaufmann B, et al. J Clin Oncol. 2015; 2Swisher EM, et al. Lancet Oncol. 2017; 3Mirza MR, et al. N Engl J Med. 2016.
Selected Toxicity≥Grade 3
Brown JS, et al. Br J Cancer. 2016.
BRCA1/2 Mutant BRCA1/2 Wild Type and Unknown
Drug No. Response No. ResponsePredominant toxicity
(in order of frequency)
Olaparib>100 (mostly
platinum resistant)30-60% 46
Platinum sensitive 50%Platinum resistant 4%
GI symptoms, fatigue, anemia
Rucaparib39 (all platinum
sensitive)69% 132
LOHhigh 29%LOHlow 13%
GI symptoms, fatigue, anemia, transient ALT/AST elevations
Niraparib20 (9 platinum
sensitive)40%
319
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, lymphopeniaaPlatinum responsiveness not known bIncludes triple negative breast cancer
PARPi Response Rates and Toxicities
PARP Inhibitors in BRCA+ Breast Cancer
Nadine M. Tung, MD
Beth Israel Deaconess Medical Center
Boston, MA
• 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.
PARP Inhibitors: Women with gBRCA+ Breast Cancer (Iceberg Trial: Olaparib)
gBRCA+ metastatic disease
Anthracycline,taxane resistant
PARP inhibitor daily
Standard Chemo, MD’s choice:
Capecitabine orVinorelbine orEribulin orGemcitabine
PrimaryEndpoint:
PFS
Randomized
BRAVO Trial (NCT01905592) - NiraparibEMBRACA (NCT01945775) - TalazoparibOLYMPIAD Trial (NCT02000622) - Olaparib
Randomized PARP Inhibitor Studies in Metastatic Breast Cancer: BRCA1/2
gBRCA+ metastatic disease
Anthracycline,taxane resistant
PARP inhibitor daily
Standard Chemo, MD’s choice:
Capecitabine orVinorelbine orEribulin orGemcitabine
PrimaryEndpoint:
PFS
Randomized
BRAVO Trial (NCT01905592) - NiraparibEMBRACA (NCT01945775) – TalazoparibOLYMPIAD Trial (NCT02000622) - Olaparib
Randomized PARP Inhibitor Studies in Metastatic Breast Cancer: BRCA1/2
OlympiAD Trial:
“Positive”: Increased PFS for olaparib vs chemotherapy
Results: ASCO 2017
https://www.astrazeneca.com/media-centre/press-releases/2017/lynparza-meets-primary-endpoint-in-phase-iii-trial-in-brca-mutated-metastatic-breast-cancer-17022017.html
gBRCA+TNBC or ER+
I. Adjuvant:T2 or N+
II. Neoadjuvant:Residual disease
PARP inhibitor daily X 1 yr
Placebo X 1 yr
Endpoints:DFS
DDFSOS
Randomized
After chemo and surgery
www.clinicaltrials.gov; NCT02032823.
Olaparib in Adjuvant Breast Cancer Setting: OlympiA
• 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.
Efficacy of PARP Inhibitors may be Lower in Breast Cancer pts with Prior Platinum
• …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.
Reversion Mutations
• 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.
Select Studies Combining PARPi with Platinum Chemotherapy
• Myelosuppression – limit dose chemo and PARPi
Hard to Combine Chemo and PARPi
PARP Inhibitors in Additional Solid Tumors
Trial Phase Treatment Arms Inclusion Primary Outcomes
NCT02511223 II •Olaparib•Non-gBRCA1/2 mutation or
HRD deficiency ORR
NCT02677038 II •Olaparib •Non-gBRCA1/2 mutation ORR
POLONCT02184195
III•Olaparib•Placebo
•gBRCA1/2 mutation PFS
NCT01489865 I/II •Veliparib/mFOLFOX •BRCA1/2 mutationDose limiting
toxicities
NCT01585805 II
•Veliparib•Veliparib/gemcitabine/
cisplatin•Gemcitabine/cisplatin
•BRCA1/2 or PALB2 mutation ORR
NCT02890355 II•Veliparib/FOLFIRI•FOLFIRI
•Metastatic pancreatic cancer OS
www.clinicaltrials.gov. FOLFIRI: Fluorouracil, irinotecan, leucovorin; mFOLFOX: Modified 5-fluorouracil and oxaplatin
Ongoing PARPi Trials in Pancreatic Cancer
Trial Phase Treatment Arms InclusionPrimary
Outcomes
PROfoundNCT02987543
III• Olaparib• Enzalutamide• Abiraterone
• mCRPC, progression on androgen receptor targeted therapy
• HRR deficiency in tumor tissuerPFS
NCT01078662 II • Olaparib• Malignant solid tumor (including prostate)• gBRCA1/2
Tumor response rate
TRITON3NCT02975934
III
• Rucaparib• Enzalutamide• Abiraterone• Docetaxel
• mCRPC, progression on androgen receptor targeted therapy
• BRCA1/2 or ATM mutationrPFS
TRITON2NCT02952534
II • Rucaparib• mCRPC, progression on 1 androgen receptor targeted
therapy and 1 taxane• BRCA1/2, ATM or other HR deficiency
ORRPSA response
GALAHADNCT02854436
II • Niraparib• mCRPC, progression on >1 taxane and >1 androgen
receptor targeted therapy• Tumor w/ DNA repair anomalies
ORR
NCT01576172 II• Veliparib/abiraterone• Abiraterone
• mCRPC, progression on androgen deprivation therapy PSA response
www.clinicaltrials.gov.
Ongoing PARPi Trials in Prostate Cancer
Improving Patient Outcomes with PARP Inhibitors: Case-based Treatment Strategies for the Oncology Nurse
Lisa Arvine, RN, MSN, ANP-BC, WHNP-BCDana-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
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.
How Do I Procure PARP Inhibitors for My Patients?
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
Inheritable
Mutation in egg or sperm
All cells affected in
children
Adapted from https://www.cancer.org/cancer/cancer-causes/genetics/family-cancer-syndromes.html.
Somatic vs. Germline Mutations
Not Inheritable
Mutation only found in tumor
Unaffected children
FDA Prescribing Information.
Common Adverse Effects of PARP Inhibitors
*Although rare, can be delayed and life threatening
• Changes in kidney function tests
• Shortness of breath
• Anemia
• Arthralgias/mylagias
• Rash
• Myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia (AML)*
• Fatigue
• Nausea and/or vomiting
• Decreased appetite
• Dysgeusia
• Abdominal pain
• Myelosuppression
FDA Prescribing Information.
Drug Specific Adverse Effects
Rucaparib• Constipation
and/or diarrhea• Changes in liver
function tests• Increased
cholesterol levels
Olaparib• Indigestion/heartburn• Rhinorrhea • Pneumonitis
Niraparib• Palpitations• Mucositis/dry
mouth• Increase in AST/ALT• Urinary tract
infections• Hypertension• Headache/dizziness
FDA Prescribing Information.
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.
•Prior to initiating PARP inhibitor, prior chemotherapy adverse effects should have resolved to <Grade 1
Anemia
•Rule out other causes of anemia (iron deficiency)
•Transfuse as needed
•Dose interruption or dose reduction
Thrombocytopenia
•First occurrence: Hold until platelets >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 Hematologic Adverse Effects Associated with PARP Inhibitors?
FDA Prescribing Information.
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
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?
FDA Prescribing Information; NCCN Cancer-Related Fatigue Guidelines Version 1.2017; https://radiopaedia.org/articles/hypersensitivity-pneumonitis.
How Do I Manage Adverse Effects Associated with PARP Inhibitors?Pneumonitis• Symptoms include cough, shortness of breath,
fatigue and weight loss
• Discontinue drugFatigue• Monitor for anemia• Encourage periods of rest and activity• Maintain good nutrition • Stay well hydrated• Manage stress• Consider dose interruption or dose reduction
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: JGAugust 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 olaparibSeptember 23, 2014• Olaparib restarted at 300 mg BID• CBC/d weeklyOctober 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
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
Case Study 2: DSDecember 28, 2016 • Initiated on olaparib 400 mg BIDJanuary 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 reviewedJanuary 25, 2017• Patient presented with similar symptoms despite recommendations as
above• Dose reduced to 300 mg BID
• 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.
Summary