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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


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


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 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





Cediranib

Olaparib



AZ1775DNA

Mitosis

Active

Inactive


Cediranib

Olaparib



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)


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)


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


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


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


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


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


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?


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

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