Megan May, Pharm.D., BCOP - s3.proce.com

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Ovarian Cancer: Implications for the Pharmacist

Megan May, Pharm.D., BCOP

Objectives

Describe the etiology and pathophysiology of o arian cancerovarian cancer

Outline the efficacy and safety of treatment options for ovarian cancer

Explain the mechanism of action of poly ADP ribose polymerase inhibitors (PARP inhibitors) available for ovarian cancer

Explain how to evaluate the appropriate selection of therapy for specific ovarian cancer patients

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Epidemiology

5th most frequent cause of death in women

Incidence in 2018 New cases: 22,240

Deaths: 14,070

Primarily post-menopausal disease Median age at diagnosis: 65-69 years old Median age at diagnosis: 65 69 years old

Caucasians > African American

National Cancer Institute. 2018.

Etiology/Pathogenesis

Sporadic ovarian cancer etiology unknownM (85 90%) Most common type (85-90%)

Familial and hereditary syndromes Less common type (10-15%)

“Incessant ovulation” theory Risk of developing ovarian cancer is related to number

of ovulatory cycles

Tumor suppressor genes BRCA1, BRCA2, p53

National Cancer Institute. 2018.

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Pathology

Epithelial adenocarcinomaS Serous

Mucinous

Endometroid

Clear-cell

Germ-cell tumor

Sex-cord stromal

Metastatic from other malignancies

Risk Factors

Early menarche, late menopause and nulliparity

Increased age

Prolonged use of ovulatory‐stimulating drugs

Environmental and dietary factors

Residence in North American or Northern Europe

C i Caucasian race

Genetic factors

Hormone replacement therapy

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Hereditary Risk

F il Hi t f O i C Lif ti Ri kFamily History of Ovarian Cancer Lifetime Risk

None 1.4 – 1.8%

1 first degree relative 3 – 5%

2 first-degree relatives 7 – 9%

Lynch Syndrome 6 – 10%

K BRCA 1 d/ BRCA 2 10 80%Known BRCA 1 and/or BRCA 2 germline mutation

10 – 80%

Ovarian Cancer Research Fund Alliance: Risk Factors. https://ocrfa.org/patients/about-ovarian-cancer/risk-factors/

Favorable Factors

Multiple pregnancies

f Breastfeeding

Use of prolonged oral contraceptives

Tubal ligation

Prophylactic oophorectomy

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Screening

No effective screening test for ovarian cancer

/ f Low/standard risk (not familial or hereditary) Annual physical and pelvic examination

High risk (hereditary ovarian cancer, BRCA‐1 or BRCA‐2 positive) Pelvic examination, transvaginal ultrasound and

CA‐125 every 6‐12 months starting at age 25‐35

Gynecol Oncol 2007; 104:S14. Abstract 10

Prevention

Oral contraceptives Use for five or more years decreases risk of ovarian

cancer by 50% or more

Longer the use, greater the protection Protection can continue for up to 30 years after stopping use

Prophylactic oophorectomy Decreases risk of ovarian cancer in high‐risk patients

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Signs and Symptoms

Bloating Pel ic or abdominal pain Pelvic or abdominal pain Eating satiety Urinary symptoms (frequency or urgency) GI symptoms Pulmonary symptoms Unilateral or bilateral, solid, cystic and/or complex

pelvic or adnexal masses CA-125 highly elevated

Staging

International Federation of Gynecologic Oncologists (FIGO) and AJCC staging s stems (stages I IV)(FIGO) and AJCC staging systems (stages I-IV)

Grade 1: well differentiated

2: moderately differentiated

3: poorly differentiated

AJCC Cancer Staging Manual, Sixth Edition (2002)

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FIGO Staging

Stage I Growth limited to the ovaries

Stage II Growth involving one or both ovaries with pelvic extension

Stage III Tumor involving one or more ovaries with tumor outside the pelvis and/or

positive retroperitoneal or inguinal lymph nodes Superficial liver metastases Tumor limited to pelvis but malignant extension to small bowel or

omentumomentum

Stage IV Growth involving one or more ovaries with distant metastases Parenchymal liver metastases Pleural effusion must have positive cytology

AJCC Cancer Staging Manual, Sixth Edition (2002)

Prognosis

Stage of disease

f f

Stage of Disease % of Cases 5-year Survival

Volume of residual disease at time of surgery

Histologic subtype and grade

CA-125

I 23 90%

II 13 70%

III 47 39 – 59%

IV 16 17%

Principles and Practice of Gyn Oncol: 3rd Ed.

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Primary Treatment (Stages I-II)

Comprehensive surgical stagingO i l < 1 id l di Optimal: < 1 cm residual disease

Suboptimal: > 1 cm residual disease

Adjuvant combination chemotherapy Taxane + platinum

Number of cycles (3 or 6) varies by stage

Observation in stage 1A or 1B

PDQ® Adult Treatment Editorial Board. PDQ Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated 07/19/2018. Available at: https://www.cancer.gov/types/ovarian/patient/ovarian-epithelial-treatment-pdq. Accessed 09/04/2018.

GOG-157

Early stage ovarian cancer, high-risk features (n = 457)(n = 457)

Randomized following surgery to 3 vs. 6 cycles of paclitaxel + carboplatin

Recurrence rate 33% lower in patients treated with 6 cycles (HR: 0.627, not statistically significant)

Grade 2 neurotoxicity in 2% vs. 11% patients

Bell J, et al. Gynceol Oncol. 2006;102(3):432-439.

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ICON-1 Trial

Early stage, high-grade, or surgically unstagedt mors (n = 477)tumors (n = 477)

Randomized, prospective, multi-center

Randomized following surgery to 6 cycles of platinum-based chemotherapy vs. observation

5-year survival Progression-free survival (PFS)

Platinum x 6 79% 73%

Observation 70% 62%

Trimbos JB, et al. J Natl Cancer Inst. 2003;95(2):105-112.

ACTION Trial

Randomized, prospective, multi‐center trial, early stage high‐grade tumors only (n = 448)g g y ( )

Stage IA or IB well‐differentiated tumors excluded Following surgery, patients randomized to receive 4

cycles of platinum‐based chemotherapy vs. observation Included grade 2‐3 tumors only At median follow‐up 5.5 years, no statistical difference

in overall survival (OS) or PFS( ) Statistically significant survival benefit only seen in

sub‐group analysis of patients who did not undergo optimal surgical staging

Trimbos JB, et al. J Natl Cancer Inst. 2003;95(2):105-112.

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Advance Stage (Stages III-IV)

Comprehensive surgical staging

f Six cycles of adjuvant combination chemotherapy with taxane + platinum or liposomal doxorubicin + carboplatin Intraperitoneal chemotherapy may be an option in

stage II or III

O ll d h h Occasionally, neoadjuvant chemotherapy


Adjuvant Chemotherapy

GOG-111 Paclitaxel + cisplatin improves median survival Paclitaxel + cisplatin improves median survival

compared to cyclophosphamide + cisplatin

GOG-158 Paclitaxel + carboplatin preferred over paclitaxel +

cisplatin due to equal efficacy and reduced toxicity

SCOTROC trial Docetaxel is equally efficacious and less neurotoxic

than paclitaxel when given in combination with carboplatin

Muggia F, et al. JCO. 2000;18(1):106-115.Bookman MA, et al. Int J Gynecol Cancer. 2003;13(6):735-740.Vasey PA, et al. J Natl Cancer Inst. 2004;96:1682-1691.

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Cisplatin versus Carboplatin

Neurotoxicity Nephrotoxicity N/V

In patients with optimally resected stage III ovarian cancer

Cisplatin +++*paclitaxel 24h infusion

+++ +++

Carboplatin +*paclitaxel 3h infusion

+ ++

Ozols RF JCO 2003;21:3194-3200; GOG 158

Complete remission and overall survival not different between cisplatin/paclitaxel and carboplatin/paclitaxel

Carboplatin regimen easier to administer

Paclitaxel versus Docetaxel

NeurotoxicityG d 2 & 3 h i h li l Greater grade 2 & 3 neuropathy with paclitaxel

Neutropenia Greater grade 4 neutropenia with docetaxel

Edema Greater with docetaxel

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IP Therapy

Patient selection Stage IIIC (optimal surgical cytoreduction) Good performance status No history of prior bowel surgery or bowel surgery at the time of

primary therapy

Benefits Substantial improvement in overall survival

Risks Infection Leukopenia Dehydration, electrolyte abnormalities Catheter malfunction Abdominal pain

Armstrong DK, et al. N Engl J Med. 2006;354:34-43.

GOG-172

Stage IIIC ovarian and primary peritoneal cancer and optimal s rgical c tored ction were and optimal surgical cytoreduction were randomized to one of the following (n = 429): IV regimen Paclitaxel 135 mg/m2 IV over 24 hours on Day 1 + cisplatin

75 mg/m2 IV on Day 2 every 3 weeks

IP regimen IP regimen Paclitaxel 135 mg/m2 IV over 24 hours on Day 1 + cisplatin

100 mg/m2 IP on day 2 + paclitaxel 60 mg/m2 IP on day 8 every 3 weeks


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GOG-172

Median PFS and OS at five years significantly improved for patients on IP treatment arm (18.3 vs. 23.8 months and 49.7

6 6 h l )vs 65.6 months, respectively) Grade 3 and 4 toxicities were significantly worse in patients

treated with IP therapy Only 42% of patients randomized to IP therapy completed six

cycles of treatment (median=3)

Patients unable to tolerate IP therapy were switched to the IV treatment arm

QOL was significantly worse for patients in the IP arm while on treatment At 12 months, there was no difference in QOL between the two

groups


Bevacizumab

FDA-approved in combination with liposomal doxorubicin paclitaxel or topotecandoxorubicin, paclitaxel, or topotecan OCEANS Trial AURELIA Trial

Bevacizumab in combination with paclitaxel + carboplatin GOG-0213

Bevacizumab monotherapy GOG-0170D CCC-PHII-45


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GOG-218

Phase III randomized, double‐blind trial Patients with stage III or IV, any gross residual disease Patients with stage III or IV, any gross residual disease

(n = 1873) Following surgery, patients were randomized standard

chemotherapy (paclitaxel + carboplatin) cycles 1‐6 and either Placebo (cycle 2‐5) followed by placebo every 3 weeks for

15 months B b 15 /k ( l 2 5) f ll d b l b Bevacizumab 15 mg/kg (cycle 2‐5) followed by placebo every 3 weeks for 15 months

Bevacizumab 15 mg/kg (cycle 2‐5) followed by bevacizumab 15 mg/kg every 3 weeks for 15 months

Burger RA, et al. J Clin Oncol. 2010;28:18S

GOG-218

Statistically significant increase in PFS for patients treated on the chemotherapy + bevacizumab + treated on the chemotherapy + bevacizumab + bevacizumab maintenance (14.1 months) vs. chemotherapy + bevacizumab + placebo maintenance (11.2 months) vs. chemotherapy alone (10.3 months) (HR=0.72)

Preliminary OS data shows no difference between groups

No difference in QOL detected between any of the three groups

Burger RA, et al. J Clin Oncol. 2010;28:18S

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ICON-7

Phase III, randomized, open label

Patients with stage I‐IV, optimal or suboptimal disease (n=1528)

Following surgery, patients were randomized Standard chemotherapy

Chemotherapy + bevacizumab 7.5 mg/kg every 3 weeks followed by bevacizumab 7.5 mg/kg maintenance every 3 weeks for 12 cycle (total one year of bevacizumab)

Perren TJ, et al. N Engl J Med. 2011;365:2484-2496.

ICON-7

At 42 months, the median PFS was modestly improved in the treatment arm vs the control arm improved in the treatment arm vs. the control arm (24.1 months vs. 22.4 months, HR=0.81)

Effect of bevacizumab was greater in patients at high risk for progression (PFS 18 months vs. 14.5 months)

Median OS was improved in the high risk patient p g ppopulation (36 months vs. 28 months)

Toxicity was greater in the bevacizumab treated patients

Perren TJ, et al. N Engl J Med. 2011;365:2484-2496.

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Recurrent, Refractory, and Resistant Ovarian Cancer

60‐80% of ovarian cancer patients

f Length of subsequent remissions is shorter than the initial remission

Goal of treatment Improve/eliminate symptoms

Achieve an objective response

Improve quality of life

Delay time to symptomatic disease

Prolong survival if possible


Definitions

Platinum‐sensitive disease Initial response to platinum Duration of initial remission > 6 months Longer the initial remission, the greater the likelihood of responding to

second and third‐line agents Probability of response to chemotherapy is 30% or more

Platinum‐resistant disease Initial response to platinum Duration of initial remission < 6 months P b bilit f t dditi l t t t i 10 15% Probability of response to additional treatment is 10‐15%

Primary progressive (platinum‐refractory) disease No response and/or progression of disease during primary therapy with

platinum Worst prognosis Probability of response to additional chemotherapy <10%


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Recurrent Ovarian Cancer

Platinum-containing chemotherapy regimens

Bevacizumab

Chemotherapy and/or bevacizumab

PARP inhibitors

Clinical trial

Cytoreductive surgery Cytoreductive surgery


Platinum

Recurrent Ovarian Cancer

Sensitive Resistant• Cisplatin/Carboplatin + paclitaxel

• Carboplatin + liposomal doxorubicin

• Carboplatin + gemcitabine +/- bevacizumab

• Cisplatin + gemcitabine

• Docetaxel

• Liposomal doxorubicin

• Gemcitabine + docetaxel

Et id ( l)• Carboplatin + albumin-bound paclitaxel

• Carboplatin + docetaxel

• Carboplatin

• Cisplatin

• Can consider abdominal radiotherapy

• Etoposide (oral)

• Topotecan

• Dose-dense paclitaxel

• Addition of bevacizumab


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PARP Inhibitors

Poly ADP-ribose polymerase inhibitorDNA i h i DNA repair mechanism

BRCA mutated cells more dependent on this mechanism

Directly inhibits PARP 1, 2, 3 and increases formation of PARP-DNA complexes, preventing DNA repair cell death

FDA approved PARP inhibitors FDA- approved PARP inhibitors Rucaparib (Rubraca®)

Olaparib (Lynparza®)

Niraparib (Zejula®)


FDA-Approved Ovarian Cancer Indications

Rucaparib Treatment of advanced ovarian cancer with gBRCA or sBRCA ≥2 prior lines of chemotherapy Maintenance treatment of recurrent ovarian cancer in complete or

partial response to platinum-based chemotherapy

Olaparib Treatment of advanced ovarian cancer with gBRCA ≥3 prior lines of chemotherapy Maintenance treatment of recurrent ovarian cancer in complete or Maintenance treatment of recurrent ovarian cancer in complete or


Niraparib Maintenance treatment of recurrent ovarian cancer in complete or


Rubraca [prescribing information]. Clovis Oncology. 2017.Lynparza [prescribing information]. AstraZenca. 2018.Zejula [prescribing information]. Tesaro. 2018.

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FDA-Approved Dosing

Rucaparib 600 mg by mouth twice daily 600 mg by mouth twice daily Tablet available: 200 mg, 250 mg, 300 mg

Olaparib 400 mg capsule by mouth twice daily Capsule available: 50 mg

300 mg tablet by mouth twice daily Tablet available 100 mg and 150 mg Tablet available: 100 mg and 150 mg

Niraparib 300 mg by mouth once daily Capsule available: 100 mg

Rubraca [prescribing information]. Clovis Oncology. 2017.Lynparza [prescribing information]. AstraZenca. 2018.Zejula [prescribing information]. Tesaro. 2018.

TreatmentA i i i l d i h i k h

Treatment versus Maintenance Therapy

An initial treatment used in attempt to shrink the current tumor

Maintenance therapy Continuing to treat after completion of standard round

of chemotherapy U d t id l th ’ t Used to avoid or slow the cancer’s return

Slow the growth of advanced cancer after the initial treatment

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Benefits

Risk/Benefits of Maintenance Therapy

May help keep cancer from coming back

May slow down cancer growth

Disadvantages Side effects

Treatment cost Treatment cost

More doctor visits

Limited information on long term side effects and benefits for each individual

All have a similar side effects, but some are more common and/or more se ere in one ers s another

PARP Inhibitor Side Effects

common and/or more severe in one versus another

Acute myeloid leukemia/myelodysplastic syndrome has been reported in 0.5%-2% of patients

Thompson LA. Oncology Nurse Advisor. 2017.

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ARIEL2: Rucaparib

Outcome BRCA Mutationn = 40

BRCA Wild-Type and LOH High

82

BRCA Wild-Type and LOH Low

70n = 82 n = 70

ORR, % 80 29 10

PFS, monthsp value (vs LOH-low)

12.8

<0.0001

5.7

0.011

5.2

-

Duration of response, months

p value (vs

9.2

0 013

10.8

0 022

5.6

-p value (vs LOH-low)

0.013 0.022 -

Swisher EM, et al. Lancet Oncol 2017;18:75-87.

LOH = loss of heterozygosityORR = objective response rate

ARIEL3: Rucaparib

Outcome BRCA Mutation Overall Study Population

Rucaparib Placebo Rucaparib Placebon = 130 n = 66 n = 375 n = 189

Median PFS, months

16.6 5.4 13.6 5.4

Coleman RL, et al. Lancet 2017;390(10106):1949-1961.

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Rucaparib Adverse Effects in ≥ 20% of Patients

Adverse Effects All Grades (%)n = 377

Grades 3/4 (%)n = 377

Nausea 77 5

Vomiting 46 4

Constipation 40 2

Diarrhea 34 2

Abdominal Pain 32 3

Asthenia/Fatigue 77 11

Anemia 44 25

Thrombocytopenia 21 5

Dysgeusia 39 0.3

Decreased appetite 39 3

Dyspnea 21 0.5

Swisher EM, et al. Lancet Oncol 2017;18:75-87.Rubraca [prescribing information]. Clovis Oncology. 2017.

Rucaparib Laboratory Abnormalities in ≥ 35% of Patients

Laboratory Parameter All Grades (%)n = 377

Grades 3/4 (%)n = 377

Increase in creatinine 92 1

Increase in ALT 74 13

Increase in AST 73 5

Increase in cholesterol 40 2

Decrease in hemoglobin 67 23

Decrease in lymphocytes 45 7

Decrease in platelets 39 6

Decrease in absolute neutrophil count 35 10

Swisher EM, et al. Lancet Oncol 2017;18:75-87.Rubraca [prescribing information]. Clovis Oncology. 2017.

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SOLO-2: Olaparib

Outcome Olaparibn = 196

Placebon = 99

PFS, months 19.1 5.5

Grade 3 or 4 adverse effects 18% 8%

Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):1274-1284.

Olaparib Adverse Effects in ≥ 20% of Patients

Adverse Effects All Grades (%) Grades 3/4 (%)

Olaparibn = 195

Placebon = 99

Olaparibn = 195

Placebon = 99

Anemia 44 9 20 2

Nausea 76 33 3 0

Vomiting 37 19 3 1

Diarrhea 33 22 2 0

Stomatitis 20 16 1 0

Nasopharyngitis/upper respiratory infection/sinusitis/rhinitis/influenza

36 29 0 2

Fatigue 66 39 4 2

Decrease appetite 22 11 0 0

Arthralgia/myalgia 30 28 0 0

Dysgeusia 27 7 0 0

Headache 26 14 1 0

Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):1274-1284.Lynparza [prescribing information]. AstraZenca. 2018.

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Olaparib Laboratory Abnormalities in ≥ 25% of Patients

Laboratory Parameter All Grades (%) Grades 3/4 (%)

Olaparib Placebo Olaparib Placebon = 195 n = 99 n = 195 n = 99

Increase in mean corpuscular volume

89 52 - -

Decrease in hemoglobin 83 69 17 0

Decrease in leukocytes 69 48 5 1

Decrease in lymphocytes 67 37 11 1

Decrease in absolute neutrophil 51 34 7 3count

Increase in serum creatinine 44 29 0 0

Increase in platelets 42 22 2 1

Pujade-Lauraine E, et al. Lancet Oncol. 2017;18(9):1274-1284.Lynparza [prescribing information]. AstraZenca. 2018.

NOVA: Niraparib

Outcome BRCA Mutation BRCA Wild-Type

Niraparib Placebo Niraparib Placebon = 138 n = 65 n = 234 n = 116

Median PFS, months

21 5.5 12.9 3.8

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.

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Niraparib Adverse Effects in ≥ 20% of Patients


Niraparib 367

Placebo 179

Niraparib 367

Placebo 179n = 367 n = 179 n = 367 n = 179

Thrombocytopenia 61 5 29 0.6

Anemia 50 7 25 0

Neutropenia 30 6 20 2

Nausea 74 35 3 1

Constipation 40 20 0.8 2

Vomiting 34 16 2 0.6

Abdominal pain/distention 33 39 2 2

Mucositis/stomatitis 20 6 0.5 0

Diarrhea 20 21 0.3 1

Fatigue/asthenia 57 41 8 0.6

Mirza MR, et al. N Engl J Med. 2016;375:2154-2164.Zejula [prescribing information]. Tesaro. 2018.

Niraparib Adverse Effects in ≥ 20% of Patients



Decreased appetite 25 15 0.3 0.6

Headache 26 11 0.3 0

Nasopharyngitis 23 14 0 0

Dyspnea 20 8 1 1

Rash 21 9 0.5 0

Hypertension 20 5 9 2Hypertension 20 5 9 2


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Niraparib Laboratory Abnormalities in ≥ 25% of Patients

Laboratory Parameter All Grades (%) Grades 3/4 (%)


Decrease in hemoglobin 85 56 25 0.5

Decrease in platelet count 72 21 35 0.5

Decrease in WBC count 66 37 7 0.7

Decrease in absolute neutrophil count

53 25 21 2

Increase in AST 36 23 1 0

Increase in ALT 28 15 1 2


Summary

Clinical staging is important in determining the appropriate treatmentappropriate treatment

New advances for patients with ovarian cancer with the PARP inhibitors Olaparib and rucaparib is approved in treatment and

maintenance

Ni ib i d i i Niraparib is approved in maintenance

Treatment should always be individualized

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Ovarian Cancer: Implications for the Pharmacist

Megan May, Pharm.D., BCOP

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Megan May, Pharm.D., BCOP - s3.proce.com