Transcript PowerPoint slides - Research To Practice

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.
Oncology Grand Rounds
Ovarian Cancer
Nurse and Physician Investigators
Discuss New Agents, Novel Therapies
and Actual Cases from Practice
Friday, April 29, 2016
12:15 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
Oncology Grand Rounds Series
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
Courtesy of Christiana Care Health System
Module 1:
Biology of Ovarian Cancer;
BRCA Testing and
“BRCAness”
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
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
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
NCCN Guidelines: RAD51D Mutation
Ovarian cancer is separated into
histological categories
Low grade
High grade
Serous
Mucinous
Specific molecular features define
these categories and shape clinical
trial design:
Mucinous tumors
KRAS mutations
Endometrioid
Clear cell
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
Courtesy of Ursula Matulonis, MD
PARP and Base Excision Repair
DNA damage
NAD+
PARP
poly(ADP-ribose)
PARP
PARG
PARP recruitment
PARP activation and
assembly of repair factors
PARP
XRCC1
PAR degradation via PARG
PNK 1
XRCC1 LigIII
LigIII
pol β
PNK 1
End processing,
gap filling and ligation
Adapted from Vergote, ND; Khanna et al, 2001; Sanchez-Perez, 2006; Kennedy et al, 2006.
Mechanism of Cell Death from Synthetic
Lethality Induced by PARP Inhibition
Adapted from Iglehart JD, Silver DP. N Engl J Med 2009;361(2):189-91.
Mechanism of Cell Death from Synthetic
Lethality Induced by PARP Inhibition
Courtesy of Jenny C Chang, MD
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
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.
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
“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
Module 2:
Key Issues in Up-Front
Management
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
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
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
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
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
Long-Term
Survival
15%
80% Experience Recurrence
Recurrence
Second-Line Treatment
NCCN Clinical Practice Guidelines for Ovarian Cancer Version 2.2015; NCCN 2012; NCI 2012
Targeted Tx
Clinical Trials
Intravenous versus Intraperitoneal
Administration of Cisplatin*
Pharmacokinetics
IV CDDP 100 mg/m2
IP CDDP 90 mg/m2
Peritoneal
fluid
Plasma
AUC
AUC
Peritoneal
fluid
Plasma
* Adapted from Howell SB et al. Ann Intern Med 1982;97(6):845-851.
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
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
General Approach to Treatment of
First or Second Recurrence
Platinum
refractory/resistant
Platinum
sensitive
Platinum-free interval
<6 months
Platinum-free interval
>6 months
Nonplatinum treatment
+/- Bevacizumab
(Doublet)
Platinum
retreatment
+/- Bevacizumab
(Triplet)
NCCN Clinical Practice Guidelines for Ovarian Cancer Version 2.2015.
AURELIA (GINECO)
Physician’s
choice: SOC or
bevacizumab
15 mg/kg q3w
Chemotherapy
to progression
Platinumresistant
OC, PP, FTC, (PFI
<6 months)
Prior
bevacizumab
allowed
n = 361
Chemotherapy
to progression
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
SOC
Primary endpoint:
PFS
Secondary
endpoints:
ORR, PFIbio, OS,
QoL, safety
ClinicalTrials.gov identifier: NCT00976911
Pujade-Laurain E et al. Proc ASCO 2012;Abstract LBA5002; J Clin Oncol 2014;32(13):1302-8.
GOG-0213: Response and Survival with
Carbo-Pac + Bev in Platinum-Sensitive,
Recurrent Ovarian Cancer
Percent (%)
PFS: Hazard ratio = 0.61, p < 0.0001
OS: Hazard ratio = 0.83, p = 0.56
Coleman RL et al. Proc SGO 2015;Abstract 3.
N = 509
(RECIST)
P < 0.0001
Module 3:
PARP Inhibitors in
the Treatment of
Metastatic Disease
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 antiangiogenic agents
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
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
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
http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm427598.htm
Olaparib package insert
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
Audeh MW et al. Lancet 2010;376(9737):245-51.
100 mg PO BID
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;33:244-250.
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
Tumor response rate
Patients with OC
(n = 193)
31.1%
CR
3%
PR
28%
SD ≥ 8 weeks
33%
Kaufman B et al. J Clin Oncol 2015;33:244-50.
Maintenance Olaparib: Study 19
Patients
• Platinum-sensitive highgrade serous OC
• ≥2 previous platinum
regimens
• Maintained PR or CR after
last platinum regimen
R
Olaparib
400 mg BID, orally
(n = 136)
Placebo
(n = 129)
Randomized 1:1
Primary endpoint
82 sites in 16 countries
PFS by RECIST
Secondary endpoints
TTP by CA-125 (GCIG criteria) or RECIST, OS, safety
Ledermann et al. Proc ASCO 2011;Abstract 5003; N Engl J Med 2012;366(15):1382-92.
Study 19: Progression-free survival
1.0
Median PFS (months)
0.9
Proportion of patients
progression free
Olaparib
8.4
Placebo
4.8
0.8
Hazard ratio 0.35
P<0.00001
0.7
0.6
0.5
0.4
0.3
0.2
Randomized treatment
Placebo
Olaparib 400 mg bid
0.1
0
0
3
9
12
15
18
Time from randomization (months)
At risk (n)
Olaparib 136
Placebo 129
6
104
51
23
6
0
0
72
23
7
1
0
0
Ledermann et al. Proc ASCO 2011;Abstract 5003; N Engl J Med 2012;366(15):1382-92.
Study 19: PFS for patients with BRCA mutation
(BRCAm)
1.0
Proportion of patients
progression-free
0.9
Median PFS
0.8
0.7
0.6
BRCAm (n = 136)
Olaparib Placebo
11.2 mo 4.3 mo
HR = 0.18
p < 0.00001
0.5
0.4
0.3
Olaparib BRCAm
0.2
Placebo BRCAm
0.1
0
0
3
6
9
12
15
Time from randomization (months)
Number at risk
Olaparib BRCAm
74
59
33
14
4
0
Placebo BRCAm
62
35
13
2
0
0
• 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):852-61.
Ongoing and Planned Trials of Olaparib
Maintenance for OC
Study
NCT01844986
(SOLO 1)
NCT02392676
NCT01874353
N
Phase
Setting
Treatment
III
After 1st-line platinumbased Tx
BRCA mutated
Olaparib
III
Platinum sensitive,
relapsed
sBRCAm or HRRassociated gene
mutations
Olaparib
Placebo
III
Platinum sensitive,
relapsed
BRCA mutated
Olaparib
Placebo
397
167
297
www.clinicaltrials.gov, April 2015
Primary Outcome: Cediranib/Olaparib
Significantly Increased PFS Compared to
Olaparib Alone
Proportion progression-free
+ Censored
Olaparib
PFS events
28
Median PFS
9.0 mo
p = 0.005
HR 0.42
Ced/Olap
19
17.7 mo
Cediranib/
olaparib
Olaparib
Months
Treatment Assignment
Liu J et al. Proc ASCO 2014;Abstract LBA5500.
1: Olaparib
2: Olaparib/Cediranib
Phase I/II Study of Durvalumab (MEDI4736) with
Olaparib or Cediranib
• Advanced or recurrent
solid tumors (ovarian,
triple-negative breast, lung,
prostate, colorectal)
• No prior checkpoint
inhibitor therapy
• (N = 323)
Durvalumab +
Olaparib
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
www.clinicaltrials.gov; NCT02484404
PARP Inhibitors in Clinical Trials for Ovarian
Cancer (OC)
PARP inhibitor
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-01367338)
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 highgrade 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 (KEYNOTE162)
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).
Module 4:
Prevention and
Management of Side Effects
and Toxicities of PARP
Inhibitors
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
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
Olaparib: Select Adverse Events
Pooled patient set (n = 300)
Patients receiving ≥3 lines of
prior chemotherapy (n = 223)
All grades
Grade ≥3
All grades
Grade ≥3
Nausea
65%
2%
64%
3%
Fatigue
61%
7%
58%
7%
Vomiting
39%
3%
43%
4%
Diarrhea
30%
1%
31%
1%
Anemia
28%
14%
30%
15%
Abdominal pain
26%
5%
26%
7%
Decreased
appetite
22%
1%
22%
1%
Dyspepsia
19%
0
20%
0
Dysgeusia
18%
0
16%
0
Adverse event
Matulonis U et al. Ann Oncol 2016;[Epub ahead of print].
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
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
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 therapyrelated 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
When the world says: “Give Up”
Hope whispers...
‘Try it
one more time’