1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content.

2. Oncology Grand Rounds Ovarian Cancer Nurse and Physician Investigators Discuss New Agents, Novel Therapies and Actual Cases from Practice
Friday, April 29, :15 PM – 1:45 PM
Faculty
Paula J Anastasia, RN, MN, AOCN
Lisa B Arvine, RN, MSN, ANP-BC, WHNP-BC
Robert L Coleman, MD
Kathleen Moore, MD
Moderator Neil Love, MD

3. Oncology Grand Rounds Series

8. Oncology Grand Rounds: Themes
New agents and treatment strategies: Benefits and risks
Counseling patients about side effects
Practical implementation
End-of-life care
Psychosocial issues in patient care
Supporting the supporters
Job satisfaction and burnout in oncology professionals
The oncology professional just entering practice
The bond that heals

9. Courtesy of Christiana Care Health System

10. Module 1: Biology of Ovarian Cancer; BRCA Testing and “BRCAness”

11. Discussion Topics
Histopathologic subtypes of OC and implications for clinical decision-making
Indications for BRCA testing in women with OC; role of extended panel testing; options for available assays and the role of genetic counseling, including virtual counseling
Implications of a positive BRCA mutation test result for treatment decision-making

12. Discussion Topics
Incidence of BRCA1/2 alterations and other clinically relevant genetic abnormalities in ovarian and other gynecologic cancers
Identification of BRCA-like and other genomic signatures that may predict benefit from PARP inhibition

13. 55-Year-Old Woman with Recurrent Ovarian Cancer (Ms Anastasia)
2011: Diagnosed with ovarian cancer
Enrolled on GOG-0262: Carboplatin/paclitaxel/bevacizumab x 6  maintenance bevacizumab x 1 year
Complete response
2013: Diagnosed with breast cancer
Adjuvant tamoxifen
Genetic testing: RAD51D germline mutation
Recurrent ovarian cancer
Multiple chemotherapies and surgery
Currently no evidence of disease
Married and employed as a television writer

15. NCCN Guidelines: RAD51D Mutation

16. Ovarian cancer is separated into histological categories
Low grade High grade
Specific molecular features define these categories and shape clinical trial design: Mucinous tumors KRAS mutations High-grade serous cancers Homologous recombination deficiency (HRD) is common and thus displays a high rate of platinum sensitivity Low-grade serous cancers KRAS mutations; usefulness of MEK inhibitors Clear cell cancers Chemotherapy insensitivity, PIK3CA mutations and sensitivity to VEGFR-2 inhibitors
Serous
Mucinous
Endometrioid
Clear cell
Courtesy of Ursula Matulonis, MD

17. PARP and Base Excision Repair
DNA damage
PARP
PARP recruitment
NAD+
poly(ADP-ribose)
PARP
PARP activation and
assembly of repair factors
PARP
pol β
XRCC1
LigIII
PNK 1
PARG
PAR degradation via PARG
End processing,
gap filling and ligation
PNK 1
pol β
LigIII
XRCC1
Adapted from Vergote, ND; Khanna et al, 2001; Sanchez-Perez, 2006; Kennedy et al, 2006.

18. Mechanism of Cell Death from Synthetic Lethality Induced by PARP Inhibition
Adapted from Iglehart JD, Silver DP. N Engl J Med 2009;361(2):

19. Mechanism of Cell Death from Synthetic Lethality Induced by PARP Inhibition
Courtesy of Jenny C Chang, MD

20. Examples of Available Multigene Panels
Test Name
# Genes
BRCAPlus 5
BreastNext 17
OvaNext 23
BROCA risk panel 51
myRisk 25
Breast Cancer High Risk Panel 6
BC/OC panel 21
BRCAvantage Plus 7

21. Who Will Benefit from PARP Inhibitor Treatment?
Germline
Somatic
Sporadic tumors with intact BRCA function
Hypermethylated
Alt Paths
Adapted from Coleman, 2009.
Courtesy of Robert Coleman, MD.

22. Cooling Cap Experience
Outside company (We used PenguinTM Cold Caps; New FDA approval 12/2015 for Dignicap®)
Patient has complete accountability
Time consuming and costly: $580 to rent cold cap Additional $500 if you hire a person to do the exchanges and bring dry ice: (her husband did this)
Change every 20 min x 1 hour before chemo,
Change every 30 min during chemo,
Change every 30 min x 4 hours after chemo
She did not lose her hair. No one at work knew she was on chemo — that was her goal
Courtesy of Paula J Anastasia, RN, MN, AOCN

23. “Penguin” Cooling Cap
Cold cap used during her 2nd line chemo to prevent hair loss from paclitaxel
Photos courtesy of Paula J Anastasia, RN, MN, AOCN, used with permission 2015

24. Module 2: Key Issues in Up-Front Management

25. Discussion Topics
Multidisciplinary consultation in the primary management of OC
Patient selection for neoadjuvant systemic treatment
Intraperitoneal (IP) chemotherapy: Available clinical data, tolerability and current indications
Supportive management considerations for patients receiving IP chemotherapy
Therapeutic options for platinum-sensitive and platinum-resistant metastatic disease

26. Discussion Topics
Current role, if any, of bevacizumab as a component of primary and/or maintenance therapy for newly diagnosed OC
Available efficacy and safety data guiding the use of bevacizumab alone or in combination with chemotherapy in the setting of platinum-sensitive or platinum-resistant recurrent OC
Other anti-angiogenic agents under investigation

27. 57-Year-Old Woman with Recurrent Ovarian Cancer (Ms Arvine)
10/2014: Diagnosed with ovarian cancer
Cytoreductive surgery
Carboplatin/paclitaxel
10/2015: Recurrent disease
Paclitaxel/bevacizumab  maintenance bevacizumab
Most recent scans: No evidence of disease
Married with 2 children, previously a physician assistant
Suffers from considerable anxiety over the unknowns of her health and her children’s future

29. Key Issues in the Up-Front Management of Stage III Ovarian Cancer
Rationale and supporting evidence for debulking surgery
Management of bulky disease
Neoadjuvant therapy
Systemic therapy for patients who undergo optimal debulking
Systemic therapy for patients without optimal debulking
Dose-dense chemotherapy
Intraperitoneal chemotherapy

30. Ovarian Cancer Standard of Care
Neoadjuvant Chemotherapy
Cytoreductive Surgery
75%-80% Stage III-IV
Platinum/Taxane x 6-8 Cycles
75%-80% Achieve Remission
Alternative Dosing Regimens
Surveillance
80% Experience Recurrence
Long-Term Survival
15%
Recurrence
Second-Line Treatment
Targeted Tx
Clinical Trials
NCCN Clinical Practice Guidelines for Ovarian Cancer Version ; NCCN 2012; NCI 2012

31. Intravenous versus Intraperitoneal Administration of Cisplatin*
Pharmacokinetics
IV CDDP 100 mg/m2
IP CDDP 90 mg/m2
Peritoneal
fluid
AUC
Peritoneal
fluid
AUC
Plasma
Plasma
* Adapted from Howell SB et al. Ann Intern Med 1982;97(6):

32. IP extravasation, complications
Pain during infusion is not normal
Erythema post infusion not normal
Bloating, discomfort due to abdominal “expansion” can last 2-5 days: normal
Fatigue, malaise, loss of appetite, nausea all common post IP and interfere with daily life
IP cisplatin is given after IV paclitaxel day 1; IP paclitaxel is given on day 8 — pt was not able to receive due to delay from extravasation
Courtesy of Paula J Anastasia, RN, MN, AOCN

33. Extravasation of IP Cisplatin
3 Different Patients
Upper Photo: Normal IP infusion
Lower Photos: IP extravasation, painful infusion, erythema develops day later
Obesity may make needle insertion a challenge
Photos courtesy of Paula J Anastasia, RN, MN, AOCN 2007, 2015

34. General Approach to Treatment of First or Second Recurrence
Platinum
refractory/resistant
Platinum sensitive
Platinum-free interval
<6 months
Platinum-free interval
>6 months
Platinum retreatment
+/- Bevacizumab
(Triplet)
Nonplatinum treatment
+/- Bevacizumab
(Doublet) .
NCCN Clinical Practice Guidelines for Ovarian Cancer Version

35. AURELIA (GINECO) Primary endpoint: PFS Secondary endpoints:
Physician’s choice: SOC or bevacizumab 15 mg/kg q3w
Chemotherapy to progression
Platinum-resistant
OC, PP, FTC, (PFI <6 months)
Prior bevacizumab allowed
n = 361
Arm A
Arm B
Chemotherapy to progression
SOC
Primary endpoint: PFS
Secondary endpoints:
ORR, PFIbio, OS, QoL, safety
Bevacizumab 10 mg/kg q2w* to progression
Stratification variables:
Chemotherapy regimen
Previous anti-angiogenic therapy
PFI <3 vs 3–6 months .
Chemotherapy options (physician’s choice):
Weekly paclitaxel 80 mg/m2
Topotecan (4 mg/m2 d1, 8, 15 OR 1.25 mg/m2 d1-5 q3w)
Pegylated liposomal doxorubicin 40 mg/m2 d1 q4w
*15 mg/kg q3w if combined with topotecan q3w
ClinicalTrials.gov identifier: NCT
Pujade-Laurain E et al. Proc ASCO 2012;Abstract LBA5002; J Clin Oncol 2014;32(13):

36. GOG-0213: Response and Survival with Carbo-Pac + Bev in Platinum-Sensitive, Recurrent Ovarian Cancer
PFS: Hazard ratio = 0.61, p <
OS: Hazard ratio = 0.83, p = 0.56
N = 509 (RECIST)
Percent (%)
P <
Coleman RL et al. Proc SGO 2015;Abstract 3.

37. Module 3: PARP Inhibitors in the Treatment of Metastatic Disease

38. Discussion Topics
Incorporation of olaparib into the treatment algorithm for patients with recurrent OC
BRCA mutation status and efficacy of PARP inhibitors
Available data with olaparib as maintenance therapy for patients with recurrent OC
Similarities and differences between olaparib and other PARP inhibitors under development
Potential synergy between PARP inhibitors and anti- angiogenic agents

39. 65-Year-Old Woman with a BRCA Germline Mutation and Recurrent Ovarian Cancer (Ms Arvine)
2002: Diagnosed with papillary serous ovarian cancer
Cytoreductive surgery
Carboplatin/paclitaxel
2013: Disease recurrence
Secondary cytoreductive surgery
Carboplatin/gemcitabine
Enrolled in SOLO 2 trial evaluating olaparib maintenance therapy
A retired nurse, married with 2 children

41. PARP Inhibitors in Ovarian Cancer
Structure and mechanism(s) of action of PARP inhibitors
Currently available and investigational PARP inhibitors
Clinical research findings to date
Efficacy
Side effects and toxicities
Anemia
GI toxicity
Practical clinical application of olaparib therapy
Ongoing clinical trials

42. New Agent Profile: Olaparib
FDA approval: December 19, 2014 
Mechanism of action: Small-molecule PARP inhibitor
Indication: As monotherapy for the treatment of patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer after ≥3 prior lines of chemotherapy
Dose/schedule: 400 mg (eight 50-mg capsules) twice daily until disease progression or unacceptable toxicity
Olaparib package insert

43. PARP Inhibitors Have Single-Agent Activity in Recurrent Germline BRCA (gBRCA) OC
Phase II study of single-agent olaparib in patients with recurrent gBRCA-mutated OC (N = 57)
400 mg PO BID
100 mg PO BID
Audeh MW et al. Lancet 2010;376(9737):

44. Olaparib Phase II Study
Multicenter Phase II study (N = 298 evaluable patients)
Patients with a germline BRCA1/2 mutation and recurrent cancer
Eligibility
Ovarian cancer resistant to prior platinum therapy
Breast cancer with 3 chemotherapy regimens for metastatic disease
Pancreatic cancer with prior gemcitabine
Prostate cancer with progression on hormonal and one systemic therapy
Olaparib administered: 400 mg twice per day
Primary efficacy endpoint: Tumor response rate
Kaufman B et al. J Clin Oncol 2015;33:

45. Olaparib Phase II Study
Phase II study of olaparib monotherapy (400 mg BID) in patients with recurrent gBRCA-mutated breast, ovarian, pancreatic or prostate cancer (N = 298).
193 patients with ovarian cancer
Response
Patients with OC (n = 193)
Tumor response rate
31.1% CR 3% PR
28%
SD ≥ 8 weeks
33%
Kaufman B et al. J Clin Oncol 2015;33:

46. Maintenance Olaparib: Study 19
Patients
Platinum-sensitive high-grade serous OC
≥2 previous platinum regimens
Maintained PR or CR after last platinum regimen
Olaparib
400 mg BID, orally
(n = 136) R
Placebo
(n = 129)
Randomized 1:1
Primary endpoint
PFS by RECIST
Secondary endpoints
TTP by CA-125 (GCIG criteria) or RECIST, OS, safety
82 sites in 16 countries
Ledermann et al. Proc ASCO 2011;Abstract 5003; N Engl J Med 2012;366(15):

47. Study 19: Progression-free survival
1.0
Olaparib
8.4
Placebo
4.8
Median PFS (months)
0.9
0.8
Hazard ratio 0.35
P<
0.7
0.6
Proportion of patients progression free
0.5
0.4
0.3
0.2
Randomized treatment
0.1
Placebo
Olaparib 400 mg bid 3 6 9 12 15 18
Time from randomization (months)
At risk (n)
Olaparib
136
104 51 23 6
Placebo
129 72 23 7 1
Ledermann et al. Proc ASCO 2011;Abstract 5003; N Engl J Med 2012;366(15):

48. Study 19: PFS for patients with BRCA mutation (BRCAm)
BRCAm (n = 136)
Olaparib
Placebo
Median PFS
11.2 mo
4.3 mo
HR = 0.18 p <
1.0
0.9
0.8
0.7
0.6
Proportion of patients progression-free
0.5
0.4
0.3
Olaparib BRCAm
0.2
Placebo BRCAm
0.1 3 6 9 12 15
Time from randomization (months)
Number at risk
Olaparib BRCAm 74 59 33 14 4
Placebo BRCAm 62 35 13 2
82% reduction in risk of disease progression or death with olaparib
Presented by Jonathan Ledermann et al at ASCO 2013; Lancet Oncol 2014;15(8):

49. Ongoing and Planned Trials of Olaparib Maintenance for OC
Study N
Phase
Setting
Treatment
NCT
(SOLO 1)
397
III
After 1st-line platinum-based Tx
BRCA mutated
Olaparib
NCT
167
Platinum sensitive, relapsed
sBRCAm or HRR-associated gene mutations
Placebo
NCT
297
April 2015

50. Proportion progression-free
Primary Outcome: Cediranib/Olaparib Significantly Increased PFS Compared to Olaparib Alone
+ Censored
Proportion progression-free
Cediranib/
olaparib
Olaparib
Ced/Olap
PFS events 28 19
Median PFS
9.0 mo
17.7 mo
p = 0.005
HR 0.42
Olaparib
Months
Treatment Assignment 1: Olaparib 2: Olaparib/Cediranib
Liu J et al. Proc ASCO 2014;Abstract LBA5500.

51. Phase I/II Study of Durvalumab (MEDI4736) with Olaparib or Cediranib
Durvalumab + Olaparib
Advanced or recurrent solid tumors (ovarian, triple-negative breast, lung, prostate, colorectal)
No prior checkpoint inhibitor therapy
(N = 323) R
Durvalumab + Cediranib
Primary endpoints:
Phase I: Recommended Phase II dose, safety in all patients
Phase II: Overall response rate for patients with recurrent OC
NCT

52. PARP Inhibitors in Clinical Trials for Ovarian Cancer (OC)
Ongoing trials
Veliparib (ABT-888)
Phase I: Combination studies in newly diagnosed and advanced OC
Phase III: Study of combination veliparib as induction therapy followed by maintenance veliparib in newly diagnosed Stage III/IV OC
Rucaparib (CO-338 or AGO14699 or PF )
Phase I/II: As monotherapy in BRCAm-positive OC
Phase II: As monotherapy in relapsed OC (ARIEL2)
Phase III: As switch maintenance after platinum in relapsed high-grade serous OC (ARIEL3)
Niraparib (MK4827)
Phase I/II: Niraparib and/or bevacizumab in HRD platinum-sensitive OC (AVANOVA)
Phase I/II: Niraparib and pembrolizumab in recurrent OC (KEYNOTE-162)
Phase II: Niraparib after ≥3 prior lines of chemotherapy Phase III: Niraparib maintenance in advanced OC
Talazoparib
(BMN 673)
Phase I or II: As monotherapy or as combination therapy for advanced OC
Clinicaltrials.gov (Accessed April 2016).

53. Module 4: Prevention and Management of Side Effects and Toxicities of PARP Inhibitors

54. Discussion Topics
Prevention and management of the gastrointestinal toxicities associated with olaparib (eg, nausea, diarrhea)
Incidence of anemia in patients receiving olaparib
Incidence of myelodysplastic syndromes/acute myeloid leukemia in patients receiving olaparib
Activity of PARP inhibitors in CNS disease secondary to metastatic OC

55. 56-Year-Old Woman with a BRCA Germline Mutation and Recurrent Ovarian Cancer (Ms Anastasia)
2011: Diagnosed with OC
Optimal debulking surgery followed by chemotherapy
One year later: Recurrent disease
Chemotherapy
Surgery
Chemotherapy with bevacizumab
1/2015: Received fourth-line olaparib 400 mg BID
Decreased to 200 mg BID due to anemia
A homemaker

56. Olaparib: Select Adverse Events
Pooled patient set (n = 300)
Patients receiving ≥3 lines of prior chemotherapy (n = 223)
All grades
Grade ≥3
Nausea
65% 2%
64% 3%
Fatigue
61% 7%
58%
Vomiting
39%
43% 4%
Diarrhea
30% 1%
31%
Anemia
28%
14%
15%
Abdominal pain
26% 5%
7 %
Decreased appetite
22%
Dyspepsia
19%
20%
Dysgeusia
18%
16%
Matulonis U et al. Ann Oncol 2016;[Epub ahead of print].

57. Strategies for Managing Nausea/Vomiting
Prophylactic antiemetics
Dose interruption
Dose reduction
Behavioral modification
Avoid sweet or spicy foods
Rest but do not lie flat for at least 2 hours after finishing a meal
5 five to 6 smaller meals, rather than 3 large meals, throughout the day

58. Strategies for Managing Anemia
Rule out other causes
Iron deficiency
MDS/AML
Agents that increase blood levels of olaparib
CYP3A inhibitors (fluconazole, aprepitant, etc)
Grapefruit, Seville oranges
Dose interruption
Dose reduction
Erythropoiesis-stimulating agents
Blood transfusion

59. Olaparib and MDS/AML
Overall, MDS/AML were reported in 22 of 2,618 (<1%) patients who received olaparib
The majority of MDS/AML cases (17 of 22) were fatal
The duration of therapy with olaparib in patients who developed secondary MDS/cancer therapy- related AML varied from <6 months to >2 years
All patients had received previous chemotherapy with platinum agents and/or other DNA-damaging agents
Olaparib package insert, April 2016

60. When the world says: “Give Up” Hope whispers... ‘Try it one more time’