i3 Health is pleased to make the speaker slides from this activity available for use as a nonaccredited self-study or teaching resource.

1. Enhancing Treatment Experiences in
Castration-Resistant Prostate Cancer:
The Nurse’s View
Brenda Martone, MSN, ANP-BC, AOCNP®
Nurse Practitioner
Northwestern Medicine

2. Provided by i3 Health
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judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition.
COMMERCIAL SUPPORT
This activity is supported by independent educational grants from Bayer Healthcare Pharmaceuticals and Sanofi/Genzyme.

3. Disclosures
Brenda Martone, MSN, ANP-BC, AOCNP® discloses the following
commercial relationships:
Speakers’ bureau: Astellas and Pfizer

4. Learning Objectives
CRPC = castration-resistant prostate cancer.
Identify patient and tumor characteristics that can tailor CRPC
treatment plans to individual patients
Distinguish the safety and efficacy profiles of novel therapies for
nonmetastatic and metastatic CRPC
Apply strategies to manage adverse events associated with novel
therapies for nonmetastatic and metastatic CRPC

5. Question 1
How many patients in your clinical practice have castration-
resistant prostate cancer?
a. Less than 10%
b. 15-30%
c. Over 50%
d. I don’t see patients with prostate cancer

6. Question 2
PSA = prostate-specific antigen.
A PSA doubling time <10 months is an indication of aggressive
prostate cancer
a. True
b. False

7. Question 3
ADT = androgen deprivation therapy.
Most men who start ADT will develop castration-resistant disease
in approximately 23 months
a. True
b. False

8. Question 4
RADAR = Radiographic Assessments for Detection of Advanced Recurrence; m1 = metastatic.
Crawford et al, 2018.
The RADAR III group made which of the following
recommendation(s) for serial imaging in men with M1 CRPC?
a. When PSA ≥10
b. Every 6 to 9 months in absence of PSA rise
c. When a patient develops new symptoms
d. When there is a change in performance status
e. (b), (c), and (d)
f. All of the above

9. Question 5
CT = computed tomography.
The following are treatment options for a man who has castration-
resistant disease and rising PSA but no evidence of metastatic
disease on CT scans and bone scan:
a. Enzalutamide
b. Abiraterone/prednisone
c. Docetaxel/prednisone
d. Bicalutamide
e. Unsure

10. Incidence of Prostate Cancer Compared With Other Cancers in Men
ACS, 2019.
0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 160,000 180,000 200,000
Bladder Cancer
Colon/Rectum Cancer
Lung/Bronchus Cancer
Prostate Cancer
Estimated CRPC Prevalence Among Men in the United States in 2019: 186,050

11. Prostate Cancer Progression
RT = radiation therapy.
NCCN, 2019.
Diagnosis
Elevated PSA
Biopsy
Local therapy
(surgery or
RT)
Undetectable
PSA
Rising PSA
Biochemical
recurrence

12. Progression to Castration-Resistant Prostate Cancer
M0 = nonmetastatic; HSPC = hormone-sensitive prostate cancer.
NCCN, 2019.
Biochemical
recurrence
M0 HSPC
M0 CRPC
M1 CRPC
M1 HSPC M1 CRPC

13. Definition of Castration-Resistant Prostate Cancer
NCCN, 2019.
Androgen deprivation
Castrate levels of testosterone
(<50 ng/dL)
Rising PSA

14. Prostate Cancer Progression
IV = intravenous; LHRH = luteinizing hormone-releasing hormone; LN = lymph node.
NCCN, 2019.
CRPC is classified as metastatic or nonmetastatic based on standard imaging (technetium
bone scan and CT abdomen/pelvis with IV contrast) in clinical trials
Imaging is critical to managing prostate cancer patients in order to correctly categorize and offer
all appropriate treatment options
• PSA decline
• Testosterone
<50 ng/dL
LHRH
• Castration
resistance
• No
metastatic
disease
Rising
PSA
• Metastatic
disease
• Bone, LN,
visceral
metastases
Rising
PSA

15. Median Time to Progression on LHRH Therapy
Ross et al, 2008; Scher et al, 2015.
ADT
Metastatic
Cohort
15.9 months
Nonmetastatic
Cohort
33.2 months
Retrospective analysis of 553 patients initiating LHRH therapy with metastatic (49%)
and nonmetastatic (51%) disease

16. Imaging Is Critical in Prostate Cancer Management
mCRPC = metastatic CRPC; nmCRPC = nonmetastatic CRPC; OMD = oligometastatic disease; ARPI = androgen receptor pathway inhibitor.
Lecouvet et al, 2018.

17. Risk Stratification: PSA Doubling Time
PSADT = PSA doubling time.
Smith et al, 2013; Lecouvet et al, 2018.
PSA doubling time:
Can risk stratify men with
biochemical recurrence
Predicts at what PSA level imaging
will likely show metastatic disease
Associated with risk of bone
metastasis or death, with PSADT ≤10
months considered an approximate
inflection point in risk
High risk: PSA ≥2 ng/mL, PSADT
≤10 months
Low risk: PSA <2 ng/mL, PSADT
>10 months

18. Case Study 1: John
RP = radical prostatectomy; NED = no evidence of disease.
69-year-old man
Diagnosed 5 years ago with Gleason 4+3 prostate cancer (elevated
PSA  biopsy  RP); scans NED
Diagnosed with biochemical recurrence 3 years ago; imaging
negative for metastatic disease
Starting LHRH therapy with PSA decline to 0.01 ng/mL
Recent PSA readings:
1.5 ng/mL (6 months ago)
2.0 ng/mL (3 months ago)
3.0 ng/mL (today)
Testosterone is <10 ng/dL
CT scans and bone scan negative for metastatic disease

19. Case Study 1: John (cont.)
AR = androgen receptor.
How would you treat this patient?
a. Continue on LHRH therapy
b. Continue on LHRH therapy and add bicalutamide
c. Continue on LHRH and add a second-generation AR inhibitor
d. Unsure

20. NCCN: Systemic Therapy for Nonmetastatic CRPC
NCCN = National Comprehensive Cancer Network; mo = month.
NCCN, 2019.

21. Changing Treatment Landscape for M0 CRPC
AAW = antiandrogen withdrawal.
NCCN, 2019.
Pre-2018
ADT (LHRH or orchiectomy)
Bicalutamide
AAW
Enzalutamide
Approved in July 2018
PROSPER
Prior safety and efficacy in PREVAIL
and AFFIRM
Apalutamide
Approved Feb 2018
SPARTAN
Darolutamide
Approved July 2019
ARAMIS

22. Second-Generation AR-Targeted Therapy
MFS = metastasis-free survival; AEs = adverse events.
El-Amm & Aragon-Ching, 2019; Fizazi et al, 2019.
Apalutamide Enzalutamide Darolutamide
Half-life 3-4 days 5.8 days
15.8 hours; 10 hours
for metabolite
Status FDA approved FDA approved FDA approved
Metabolism Hepatic Hepatic Hepatic
Dosage
240 mg orally once
daily
160 mg orally once
daily
600 mg orally twice
daily
Key phase 3 trial SPARTAN PROSPER ARAMIS
N (patients) 1,207 1,401 1,502
MFS vs placebo
(months)
40 vs 14.7 36.6 vs 13.6 40.4 vs 18.4
Serious AEs vs
placebo (%) 25 vs 23 24 vs 18 25 vs 20

23. SPARTAN Trial: Apalutamide in Nonmetastatic CRPC
CI = confidence interval.
Smith et al, 2018.

24. SPARTAN Trial: Apalutamide Adverse Events
Smith et al, 2018.
Adverse Event Apalutamide (N=803) Placebo (N=398)
Any grade Grade 3 or 4 Any grade Grade 3 or 4
Any adverse event 775 (96.5%) 362 (45.1%) 371 (93.2%) 136 (34.2%)
Serious adverse event 199 (24.8%) – 92 (23.1%) –
Adverse event leading to
discontinuation of the trial
regimen
85 (10.6%) – 28 (7.0%) –
Adverse event associated
with death
10 (1.2%) – 1 (0.3%) –

25. SPARTAN Trial: Apalutamide Adverse Events (cont.)
aThis category includes adverse events that occurred up to 28 days after the last dose of the trial regimen was administered.
bThese adverse events were considered by the investigators to be related to the trial regimen.
cIndicates that mental impairment disorders included the following adverse events: disturbance in attention, memory impairment, cognitive disorder, and amnesia.
Smith et al, 2018.
Adverse Event Apalutamide (N=803) Placebo (N=398)
Adverse events that occurred in ≥15% of
patients in either groupa Any grade Grade 3 or 4 Any grade Grade 3 or 4
Fatigueb 244 (30.4%) 7 (0.9%) 84 (21.1%) 1 (0.3%)
Hypertension 199 (24.8%) 115 (14.3%) 79 (19.8%) 47 (11.8%)
Rashb 191 (23.8%) 42 (5.2%) 22 (5.5%) 1 (0.3%)
Diarrhea 163 (20.3%) 8 (1.0%) 60 (15.1%) 2 (0.5%)
Nausea 145 (18.1%) 0 63 (15.8%) 0
Weight loss 129 (16.1%) 9 (1.1%) 25 (6.3%) 1 (0.3%)
Arthralgia 128 (15.9%) 0 30 (7.5%) 0
Fallsb 125 (15.6%) 14 (1.7%) 36 (9.0%) 3 (0.8 %)
Other adverse events of interest
Fractureb 94 (11.7%) 22 (2.7%) 26 (6.5%) 3 (0.8%)
Dizziness 75 (9.3%) 5 (0.6%) 25 (6.3%) 0
Hypothyroidismb 65 (8.1%) 0 8 (2.0%) 0
Mental impairment disorderc 41 (5.1%) 0 12 (3.0%) 0
Seizureb 2 (0.2%) 0 0 0

26. PROSPER Trial: Enzalutamide in Nonmetastatic CRPC
NR = not reached.
Hussain et al, 2018.

27. PROSPER Trial: Enzalutamide Adverse Events
Hussain et al, 2018.
Event
Enzalutamide Group
(N=930)
Placebo Group
(N=465)
All grades Grade ≥3 All grades Grade ≥3
Any adverse event 808 (87%) 292 (31%) 360 (77%) 109 (23%)
Any serious adverse event 226 (24%) – 85 (18%) –
Adverse event leading to
discontinuation of trial
regimen
87 (9%) – 28 (6%) –
Adverse event leading to
death
32 (3%) – 3 (1%) –

28. PROSPER Trial: Enzalutamide Adverse Events (cont.)
Hussain et al, 2018.
Event
Enzalutamide Group
(N=930)
Placebo Group
(N=465)
Adverse events of special interest
All grades Grade ≥3 All grades Grade ≥3
Hypertension 114 (12%) 43 (5%) 25 (5%) 11 (2%)
Major adverse
cardiovascular event
48 (5%) 34 (4%) 13 (3%) 8 (2%)
Mental impairment
disorders
48 (5%) 1 (<1%) 9 (2%) 0
Hepatic impairment 11 (1%) 5 (1%) 9 (2%) 2 (<1%)
Neutropenia 9 (1%) 5 (1%) 1 (<1%) 1 (<1%)
Convulsion 3 (<1%) 2 (<1%) 0 0
Posterior reversible
encephalopathy syndrome
0 0 0 0

29. Nonmetastatic CRPC: Darolutamide
Fizazi et al, 2019.

30. Darolutamide: Adverse Events of Interest
Fizazi et al, 2019.
Adverse Event
Darolutamide
(n=954)
Placebo
(n=554)
Any Grade Grade 3/4 Any Grade Grade 3/4
Fatigue or asthenic conditions 15.8% 0.6% 11.4% 1.1%
Bone fracture 4.2% 0.9% 3.6% 0.9%
Falls, including accident 4.2% 0.8% 4.7% 0.7%
Seizure, any event 0.2% 0 0.2% 0
Rash 2.9% 0.1% 0.9% 0
Weight decrease, any event 3.6% 0 2.2% 0
Dizziness, including vertigo 4.5% 0.2% 4.0% 0.2%
Cognitive disorder 0.4% 0 0.2% 0
Memory impairment 0.5% 0 1.3% 0
Change in mental status 0 0 0.2% 0
Hypothyroidism 0.2% 0 0 0
Cerebral ischemia 1.4% 0.7% 1.4% 0.7%
Coronary artery disorder 3.2% 1.7% 2.5% 0.4%
Heart failure 1.9% 0.5% 0.9% 0

31. Metastatic Castration-Resistant
Prostate Cancer

32. Genomic Testing
All men with metastatic CRPC should undergo germline testing
Tissue or blood testing sent to a lab for DNA sequencing
Acquired alterations are responsible for cancer growth. Either cancer
responds or doesn’t respond to therapy
Next-generation sequencing should be used to test the prostate cancer for
somatic mutations
Identify possible targeted treatment options
DNA = deoxyribonucleic acid.
NCCN, 2019.

33. Skeletal-Related Events and M1 CRPC
Zoledronic acid
4 mg IV every 4 weeks
Denosumab
120 mg sq every 4 weeks
Bone metastases are a common cause of morbidity in patients with
prostate carcinoma.
sq = subcutaneous.
Fizazi et al, 2011; Saad et al, 2004.

34. NCCN: Systemic Therapy for Metastatic CRPC
MSI-H = microsatellite instability-high; dMMR = deficient mismatch repair.
NCCN, 2019.

35. Metastatic CRPC Treatment Options
ECOG = Eastern Cooperative Oncology Group.
NCCN, 2019.
Second-generation AR inhibitors
Abiraterone with prednisone
Enzalutamide
Chemotherapy
Docetaxel and prednisone
Cabazitaxel and prednisone
Radium-223
Radiolabeled isotope
Symptomatic metastatic prostate
cancer to bone only
Immunotherapy
Sipuleucel-T
Men with asymptomatic or minimally
symptomatic M1 CRPC
Slowly progressing disease
No liver metastases
ECOG 0-1
Not on opioids or steroids
Pembrolizumab
dMMR

36. Options for Metastatic Prostate Cancer
NCCN, 2019.
NO SOFT TISSUE DISEASE:
Abiraterone acetate with prednisone
Cabazitaxel
Enzalutamide
Radium-223 if symptomatic bone
metastasis
Pembrolizumab for MSI-H/dMMR
Sipuleucel-T
Clinical trial
Best supportive care
SOFT TISSUE DISEASE:
Abiraterone with prednisone
Cabazitaxel
Pembrolizumab for MSI-H/dMMR
Clinical trial
Best supportive care

37. Case Study 2: Bill
HTN = hypertension; ARB = angiotensin receptor blockers; dx = diagnosed; EBRT = external beam radiation; CXR = chest x-ray.
70-year-old man
Past medical history
HTN on ARB
Hyperlipidemia on statin
Family history
Brother dx prostate cancer 67
Uncle dx prostate cancer 60
Father dx prostate cancer 58
Previous treatment
ADT and EBRT
Apalutamide M0 CRPC
Imaging
Bone scan with lesions noted in
thoracolumbar spine
CT scans of abdomen and pelvis:
sclerotic lesions noted throughout
thoracolumbar spine
CXR
ECOG 0
PSA 56 ng/mL
Testosterone <10 ng/dL

38. Case Study 2: Bill (cont.)
In your clinical practice, which of the following treatment options would
you choose for Bill for his castration-resistant metastatic prostate cancer?
a. Sipuleucel-T
b. Docetaxel/prednisone
c. Enzalutamide
d. Abiraterone/prednisone
e. Radium-223
f. Cabazitaxel/prednisone

39. Sipuleucel-T in Metastatic CRPC
Kantoff et al, 2010.
Autologous activated cellular
immunotherapy
Improved median overall survival
compared with placebo
25.8 vs 21.7 months
Adverse events more frequent in
the sipuleucel-T group:
Chills
Fever
Headache

40. Case Study 2: Bill (cont.)
sip-T = sipuleucel-T.
Imaging
Bone scan remains stable, with
lesions noted in thoracolumbar spine
CT scans of abdomen and pelvis:
sclerotic lesions noted throughout
thoracolumbar spine
0
10
20
30
40
50
60
70
80
90
Feb-18 Apr-18 Jun-18 Aug-18 Oct-18 Dec-18 Feb-19
PSA
Elects to proceed with sip-T
Completes treatment
ECOG 1 (fatigue)
PSA continues to rise
Sipuleucel-T

41. Case Study 2: Bill (cont.)
Counseled to undergo next-generation sequencing
Consider referral to genetic counselor
MLH1, MSH2, MSH6, PMS2, BRCA1/2, ATM, PALB2, CHEK2
Discussed options for treatment
Abiraterone/prednisone
Enzalutamide
Docetaxel/prednisone
Radium-223

42. Interference With Androgenic Stimulation: Abiraterone
PO = oral administration; QD = once daily; BID = twice daily; LFTs = liver function tests.
Ryan et al, 2015.
Abiraterone/prednisone
Blocks CYP17 gene
Blocks synthesis of androgens in the
tumor, testes, and adrenal gland
Decreases cortisol production
Dosing:
1,000 mg PO QD on empty stomach
Prednisone 5 mg BID with food
Side effects
Fatigue
Electrolyte imbalances
Hypertension
Fluid retention
Joint aches and pains
Diarrhea
Elevated LFTs

43. Interference With Androgenic Stimulation: Enzalutamide
Xtandi® prescribing information, 2018.
Acts at multiple sites in androgen
signaling pathway
Blocks binding of androgen to AR
160 mg PO QD
With or without food
No steroid requirement
Side effects
Fatigue/asthenia
Increased risk of falls/fractures
Dizziness/headaches/seizures
Hypertension
Nausea/constipation
Cognitive and attention disorders

44. Chemotherapy: Docetaxel
NCCN, 2019; Taxotere prescribing information, 2013.
Docetaxel 75 mg/m2 every 21 days up
to 10 cycles; prednisone 5 mg PO BID
Consider in men who are symptomatic
Short response to primary ADT
Prolongs overall survival
Side effects
Myelosuppression
Nausea/vomiting
Diarrhea/constipation
Peripheral neuropathies
Fatigue
Elevated LFTs
Partial hair loss

45. Nursing Management
NCCN, 2019; Taxotere prescribing information, 2013.
Abiraterone/prednisone and
enzalutamide
Oral medications dosed at home
Interactions with food and meds
Electrolyte and LFTs
Blood pressure monitoring
Side effect monitoring
Docetaxel and prednisone
IV chemotherapy
Antiemetics
Premedication for infusion reaction
Side effect monitoring and
management

46. Radium-223
Wilson & Parker, 2016; Xofigo® prescribing information, 2018.
One-minute monthly injection
with a radioisotope which travels
to metastatic sites in bone
Delivers targeted radiation to
(multiple) sites of bone
breakdown
Side effects: nausea, vomiting,
diarrhea, low blood counts, and
fatigue

47. Radium-223 Versus Best Supportive Care
Parker et al, 2013.

48. Radium-223: Warnings and Precautions
Parker et al, 2013; Xofigo® prescribing information, 2018.
Bone marrow suppression
Measure blood counts prior to treatment initiation and before every dose of radium-223
Discontinue if hematologic values do not recover within 6 to 8 weeks after treatment
Closely monitor patients with compromised bone marrow reserve
Discontinue in patients who experience life-threatening complications despite supportive
care measures
Ensure that men are on bone-strengthening agents
Not recommended in combination with abiraterone acetate plus prednisone
or prednisolone
Increased fractures and mortality

49. Case Study 3: Mark
Hx = history; CAD = coronary artery disease; d/t = due to.
75-year-old man with a hx of HTN, hyperlipidemia, and CAD
presenting with M1 CRPC
Treatment history following RP 10 years ago:
LHRH. Added enzalutamide for M0 CRPC. He was treated for approximately 33
months
Progressed to M1 CRPC with multiple bone lesions, retroperitoneal adenopathy, and
bone pain 2 years ago
Docetaxel and prednisone x 10 cycles. Stopped d/t hematologic toxicity. Stable
disease
Bisphosphonates added
Progression of disease with new bone lesions. No current adenopathy or soft tissue
disease. ECOG 1

50. Case Study 3: Mark (cont.)
AST/ALT = aspartate aminotransferase/alanine aminotransferase; bili = bilirubin; WNL = within normal limits; Alk phos = alkaline phosphatase.
Treated with radium-223 x 6 cycles
Follow-up imaging with stable bone lesions
CT scans with enlarging LN and 2 approximately 1-cm lesions
in the liver concerning for metastases
AST/ALT, total bili are WNL. Alk phos 455
Next-generation sequencing reveals BRCA1 mutation and
dMMR
Presenting for discussion of treatment options

51. NCCN: Systemic Therapy for Metastatic CRPC
NCCN, 2019.

52. Chemotherapy: Cabazitaxel
NCCN, 2019.
Dosage: 20 mg/m2 or 25 mg/m2
For patients who have progressed
despite prior docetaxel
Consider prednisone for healthy men
who prefer more aggressive treatment
Side effects (higher with 25-mg dose)
Febrile neutropenia
Diarrhea
Fatigue
Nausea/vomiting
Anemia
Thrombocytopenia
Sepsis
Renal failure

53. FIRSTANA: Cabazitaxel vs Docetaxel
C20 = cabazitaxel 20 mg/m2; C25 = cabazitaxel 25 mg/m2; D75 = docetaxel 75 mg/m2.
Oudard et al, 2017.

54. FIRSTANA: Notable Safety Differences
Oudard et al, 2017.
Adverse Event
C20 C25 D75
All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade ≥3
Febrile neutropenia 2.4% 2.4% 12.0% 12.0% 8.3% 8.3%
Diarrhea 32.5% 3.5% 49.9% 5.6% 37.0% 2.3%
Hematuria 20.3% 3.5% 25.1% 3.6% 3.6% 0.3%
Peripheral neuropathy 11.7% 0.3% 12.3% 0% 25.1% 2.1%
Peripheral edema 9.8% 0% 7.7% 0.3% 20.4% 1.6%
Alopecia 8.9% 0% 13.0% 0% 39.0% 0%
Nail disorders 0.3% 0% 0.8% 0% 9.0% 0.3%

55. Pembrolizumab in M1 CRPC: KEYNOTE-199
PD-L1 = programmed death-ligand 1; mets = metastasis; RECIST = Response Evaluation Criteria in Solid Tumors.
de Bono et al, 2018.

56. DNA Repair Deficiency Mutations Can Be Present and
Predict Response to PARP Inhibitors
PARP = poly(ADP-ribose) polymerase.
Mateo et al, 2015.

57. Patient-Centered Prostate Cancer Treatment
QOL = quality of life.
Science- and evidence-driven
More focus on QOL issues for men and their families
Continuously improving supportive care interventions
Hope for a cure

58. Future Considerations: Clinical Research
Huehls et al, 2015; Silvestri et al, 2019.
Immunotherapy in combination or with targeted agents
More data on watchful waiting
Refine genomic testing with more targeted treatments
PARP inhibitors

59. Key Takeaways
PSADT can risk stratify patients with nonmetastatic CRPC
The androgen receptor remains the most important driver in the continuum
of CRPC
Prostate cancer therapy is a marathon
Make sure we get the most mileage out of each treatment
More than one right sequencing strategy
Look for trial opportunities EARLY
Genomics are increasingly important for individualizing therapy
Sequencing of therapies is an active area of interest

60. References
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