This document discusses prostate cancer and germ cell tumors. It provides information on prostate cancer incidence and mortality, screening recommendations, prevention studies using 5-alpha reductase inhibitors, pathology grading, staging, risk assessment, treatment options for localized disease including active surveillance and radical prostatectomy, treatment of recurrent disease including androgen deprivation therapy, and treatment of metastatic prostate cancer with androgen deprivation therapy. It also briefly discusses current treatment recommendations for testicular cancer including seminomas and non-seminomatous germ cell tumors.

1. Prostate cancer and germ cell tumors
(testicular cancer)
Kevin Courtney, MD, PhD
Assistant Professor of Internal Medicine
Division of Hematology/Oncology
UT Southwestern Medical Center

2. Disclosures
• Research funding support from Astellas Pharma US, Inc.
(NCT02064582)

3. Educational Objectives
• To understand the mechanisms underlying the development
and progression of prostate cancer (prostatic
adenocarcinoma)
• To become familiar with current treatment options for
localized and metastatic prostate cancer and their biologic
rationale
• To become familiar with current treatment recommendations
for testicular cancer
– Seminomas
– Non-seminomatous germ cell tumors (NSGCT)

4. Prostate Cancer

5. Prostate Cancer: Incidence and Mortality
• American Cancer Society 2015 US estimates:
• 220,800 new cases of prostate cancer - #1 (excluding
squamous or basal cell skin cancer) for men and women
combined – 85% localized disease
• 27,540 deaths - # 2 for men, # 5 for men and women
combined – metastatic disease
• Lifetime probability: 1 in 7
• Focus of presentation: prostatic adenocarcinoma (setting
aside adenocarcinoma with neuroendocrine features and
small cell carcinoma of the prostate)
Siegel RL, et al. “Cancer Statistics, 2015.” CA: A Cancer Journal for Clinicians (2015) 65:5-29.

6. Prostate Cancer Screening
• Prostate Cancer Risk Factors:
– Family History, especially 1st degree relative, relatives diagnosed at age < 65
– Black ancestry
– Age
• Large Screening Studies:
– Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer screening trial
(US) (Andriole GL, et al. (2009) NEJM, 360:1310-19; Andriole GL, et al. (2012) JNCI, 104:125-32.)
• 76,685 men aged 55-74 randomized to annual PSA x 6 years + DRE x 4 years vs. control
• 7% with FH of CaP, 4% African American
• 11% vs 10% incidence of CaP at 13 years (RR 1.12, 95% CI [1.07,1.17])
• 0.4% prostate cancer – specific mortality in each group (RR 1.09, 95% CI [0.87,1.36])
• NB: ~ 50% in control group underwent PSA testing in 6th year of screening
– European Randomized Study of Screening for Prostate Cancer (ERSPC)
(Schroder FH, et al. (2009) NEJM, 360:1320-28; Schroder FH, et al. (2012) NEJM, 366:981-90)
• 182,160 men in 7 countries randomized to PSA without DRE every 4 years (every 2 years in
Sweden)
• ~ 10% vs. 6% cumulative CaP incidence at 11 years in screening vs. control group (RR 1.63, 95%
CI [1.57,1.69])
• ~ 0.4% vs. 0.5% prostate cancer mortality at 11 years, RR 0.79, 95% CI [0.68,0.91])
• ~ 20% annual rate of PSA screening in the control group
• Need to diagnose 37 additional men through screening for 1 fewer prostate cancer deaths after
11 years of follow up for men aged 55-69
Hayes JH and MJ Barry (2014) JAMA, 311:1143-49.

7. Screening recommendations of major societies
Hayes JH and MJ Barry (2014) JAMA, 311:1143-49.

8. Prostate cancer prevention studies with 5a-reductase
inhibitors
• 5a-reductase converts testosterone to the
more potent androgen
dihydrotestosterone (DHT)
• Three isoforms of 5a-reductase
• Finasteride inhibits type 1
• Dutasteride inhibits types 1 & 2
Nacusi LP and DJ Tindall. (2011) Nat Rev Urol 8:378-84.

9. Prostate cancer prevention studies with 5a-reductase
inhibitors
• Prostate Cancer Prevention Trial (PCPT) (Thompson IM, et al. (2003) NEJM, 349:215-24;
Thompson IM, et al. (2013) NEJM, 369:603-10)
– 18,880 men with PSA < 3.0 ng/mL and normal DRE randomized to finasteride 5 mg daily vs placebo
– Decreased prostate cancer incidence with finasteride (10.5% vs 14.9%) with up to 18 years of follow
up (RR 0.70; 95% CI [0.65,0.76], p<0.001)
– Increased % of Gleason 7-10 tumors with finasteride (3.5 vs 3.0%, RR 1.17, 95% CI [1.00, 1.37],
p=0.05)
– 15-year survival 78.0% vs 78.2% (HR 1.02, 95% CI [0.97,10.8], p=0.46)
• Reduction by dutasteride of prostate cancer events (REDUCE) Trial (Andriole GL, et al.
(2010) NEJM, 362:1192-202)
– 6,729 men ages 50-75 with PSA 2.5-10.0 ng/mL and negative prostate biopsy within 6 months of
enrollment randomized to dutasteride 0.5 mg daily vs placebo
– TRUS-guided prostate biopsy (10 core) at 2 and 4 years
– Relative risk reduction for prostate cancer of 22.8% (95% CI [15.2,29.8], p<0.001)
– No statistically significant difference in Gleason 7-10 tumors over 4 years, but during years 3-4, 12
dutasteride –treated vs 1 placebo-treated subjects were found to have Gleason 7-10 cancer
(p=0.003)
• No American Urologic Association (AUA) or American Society of Clinical Oncology
(ASCO) clinical practice guidelines for use of 5a-reductase inhibitors (Nacusi LP and DJ
Tindall. (2011) Nat Rev Urol 8:378-84)

10. Prostate cancer pathology: Gleason
grading
• Gleason score 2-4
essentially a thing
of the past
• > 12 Cores
Epstein JI, J Urol, 2010.

11. TNM staging system for prostate cancer
• Clinical
• T0 – no evidence of primary tumor
• T1 – Undetectable by palaption or imaging
– T1a – incidental histologic finding in < 5% of tissue resected
– T1b – incidental histologic finding in > 5% of tissue resected
– T1c – Tumor identified by needled biopsy (e.g. due to elevated PSA)
• T2 – Tumor confined within the prostate
– T2a - < ½ of 1 lobe
– T2b - > ½ of 1 lobe, not both lobes
– T2c – both lobes
• T3 – Tumor extends through the prostatic capsule
– T3a – Extracapsular extension
– T3b – Seminal vesicle invasion
• T4 – Tumor is fixed or invades adjacent structures other than SVs
• Pathologic (pT)
• pT2 – Organ confined
• pT3 – Extraprostatic extension
• pT4 – Invasion of bladder, rectum
AJCC Cancer Staging Manual, 7th Ed (2010).

12. TNM Staging System for prostate cancer
• Regional Lymph Nodes (N)
• Clinical
• NX – Not assessed
• N0 – No regional lymph nodes metastasis
• N1 – Metastasis in regional lymph nodes
• Pathologic
• pNX – Not sampled
• pN0 – None positive
• pN1 – Metastases in regional node(s)
• Distant Metastasis (M)
• M0 – None
• M1 – Distant metastasis
– M1a – Non-regional lymph node(s)
– M1b – Bone
– M1c – Other sites
AJCC Cancer Staging Manual, 7th Ed (2010).

13. Anatomic Stage / Prognostic Groups
Group T N M PSA Gleason
I T1a-c N0 M0 < 10 < 6
T2a N0 M0 < 10 < 6
T1-2a N0 M0 X X
IIA T1a-c N0 M0 < 20 7
T1a-c N0 M0 > 10 < 20 < 6
T2a N0 M0 < 20 < 7
T2b N0 M0 < 20 < 7
T2b N0 M0 X X
IIB T2c N0 M0 Any Any
T1-2 N0 M0 > 20 Any
T1-2 N0 M0 Any > 8
III T3a-b N0 M0 Any Any
IV T4 N0 M0 Any Any
Any N1 M0 Any Any
Any Any M1 Any Any
AJCC Cancer Staging Manual, 7th Ed (2010)

14. Prostate cancer staging work up
• If life expectancy < 5 years, reasonable to wait until symptoms
develop prior to treating unless high-risk disease where risk of
complications such as hydronephrosis or metastasis are
expected within 5 years
• If life expectancy > 5 years, stage and risk stratify
– Bone scan if T1 and PSA > 20 or T2 and PSA > 10 or Gleason > 8 or T3,
T4 or symptomatic
– Pelvic CT or MRI if T3, T4 or T1-T2 and probability of LN involvement >
20% by nomogram
– I scan if PSA > 7 and planning definitive treatment
• http://www.mskcc.org/cancer-care/adult/prostate/prediction-tools
NCCN Guidelines Version 3.2012

15. LOCALIZED PROSTATE CANCER

16. Prostate cancer recurrence risk
VERY LOW LOW INTERMEDIATE HIGH VERY HIGH
PSA < 10 ng/mL < 10 20-Oct > 20
and
Gleason score < 6 < 6 7 10-Aug
and
Clinical T stage < T1c T1-T2a T2b-T2c T3a T3b-T4
and
< 3 + cores
and
< 50% cancer / core
and
PSA density < 0.15
ng/mL/g
NCCN Guidelines Version 3.2012

17. Treatment Options
• Active surveillance (NB: different from observation)
• Radical prostatectomy (RP) – “open” retropubic vs robotic-assisted
laparoscopic RP
• Cryotherapy (insufficient longitudinal data for my taste)
• HIFU (not FDA approved)
• Radiation Therapy
– Brachytherapy (seeds)
– External beam – electrons
– External beam – protons
– Stereotactic radiotherapy (not yet)
• Androgen deprivation therapy and / or androgen receptor inhibitor
therapy
• Multimodality therapy

18. Very Low and Low Risk
• Active Surveillance
– PSA at least q 6 months
– DRE at least q 12 months
– Repeat biopsy at 6-18 months and at intervals thereafter
• Brachytherapy
– Contraindicated if high AUA score, prior TURP, large median lobes (where
prostate converges on bladder neck), large prostate
– Brachytherapy survival data for only about 15 years
– 125-Iodine, 103-Palladium
• EBRT
– IMRT (photons) vs protons: the “no exit dose” advantage of protons is lost
when treating deep tissue like prostate, which requires opposing beams
• Radical prostatectomy +/- PLND (yes if probability of LN
involvement > 2%)
NCCN Guidelines Version 3.2012

19. Radical Prostatectomy (RP) vs “Watchful Waiting” (WW): SPCG-4
• Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4)
• 10/89-02/99: 695 men with newly diagnosed prostate cancer stage T1b
(12%), T1c (11%), or T2 (76%) randomized to watchful waiting (348 WW)
or radical prostatectomy ( 347 RP) – prior to the era of PSA testing
• Primary endpoints: death from any cause, death from prostate cancer, risk
of metastases
• Median f/u 13.2 years
• Incidence of death at 18 years: 56.1% (RP) vs 68.9% (WW): RR 0.71 (95%
CI, 0.59 to 0.86, P<0.001)
• Number needed to treat to prevent 1 death at 18 years of f/u: 8
• Incidence of death from prostate cancer at 18 years: 17.7% (RP) vs 28.7%
(WW): RR 0.56 ((5% CI, 0.41 to 0.77, P=0.001)
Bill-Axelson A et al, (2014) NEJM, 370:932-42.

20. RP vs observation: PIVOT
• Prostate Cancer Intervention Versus Observation Trial (PIVOT):A Randomized
Trial Comparing Radical Prostatectomy Versus Palliative Expectant
Management for the Treatment of Clinically Localized Prostate Cancer
(NCT00007644)
• 731 patients, < 75 years old, clinically localized prostate cancer (stage T1-
T2NxM0, any grade, PSA < 50 ng/mL) enrolled between 1994-2010 – initiated
in the era of PSA testing
• Median age 67
• 75% detected by screening
• Median PSA 7.8
• Median f/u 10 years
• No significant difference in overall mortality (primary endpoint) or prostate
cancer-specific mortality through > 12 years of f/u
• Subset of patients with PSA > 10: RP associated with improved all-cause
mortality (P = 0.04 for interaction)
Wilt TJ, et al. (2012) NEJM, 367:203-13.

21. Intermediate risk
• Androgen suppression if life expectancy < 10 years
• EBRT +/- neoadjuvant/concommitant/adjuvant ADT (4-6
months) +/- brachytherapy
• RP +/- PLND (if predicted probability of LN involvement > 2%)
NCCN Guidelines Version 3.2012

22. High risk prostate cancer
• RP + PLND (with reasonable probability of adjuvant or salvage
RT +/- ADT)
• EBRT + 2-3 years ADT (6 months in select cases)
NCCN Guidelines Version 3.2012

23. BIOCHEMICAL RECURRENCE

24. Biochemical Recurrence
• Active surveillance vs. hormonal manipulation (anti-androgen,
GnRH agonist, GnRH antagonist)
• If choose ADT, intermittent ADT is a viable option
• Clinical trial

25. METASTATIC PROSTATE CANCER

26. Endocrine Axis in Prostate Cancer
Hypothalamus
Pituitary
Adrenals
Testes
Prostate
ACTH
LHRH (pulsatile)
LH
T
T DHT
AR
X
X
X

27. Methods of androgen deprivation therapy (ADT)
• Orchiectomy
• LHRH agonist / antagonist
• Estrogen (cardiovascular and
thromboembolic toxicity)
• Antiandrogen
• CYP17 inhibition in the adrenal gland
• Combined androgen blockade (CAB)
• 5a-reductase inhibition to impair
conversion of T to DHT (as part of
CAB)
Hypothalamus
Pituitary
Adrenals
Testes
Prostate
ACTH
LHRH (pulsatile)
LH
T
T DHT
AR
X
X
X

28. Androgen deprivation therapy (ADT) to treat
metastatic prostate cancer
• ADT leads to objective responses in 80-90% of men
(castration-sensitive prostate cancer)
• Highly variable duration of efficacy
• Median time to prostate cancer progression with ADT: 2-3
years

29. Castration-sensitive metastatic prostate cancer
• ADT (GnRH agonist + initial anti-androgen to offset transient
androgen surge OR GnRH antagonist or orchiectomy) – until
June 2014 was the standard of care for all patients
• In emergent setting, orchiectomy or ketoconazole 400 mg po
tid + hydrocortisone (30 mg qam, 10 mg qpm) and confirm
testosterone < 50 ng/mL prior to initiating GnRH agonist
therapy
• No convincing evidence for survival benefit for combined
androgen blockade with GnRH agonist + first-generation anti-
androgens

30. ADT side effects
• Hot flashes
• Loss of Libido
• Decreased sexual performance
• Gynecomastia
• Weight gain
• Decreased muscle mass
• Accelerated osteoporosis
• Increased DM
• Altered lipid profile
• Increased CV risk

31. ADT and osteoporosis
• Bisphosphonates (oral or iv) have been demonstrated to prevent bone loss
associated with ADT (pamidronate, zoledronic acid, alendronate)
• Denosumab: a fully human monoclonal antibody against receptor activator of
nuclear factor-κB ligand (RANKL)
• Patients receiving > 12 months ADT for non-metastatic prostate cancer with high
risk for osteoporosis (age > 70 or low baseline bone mineral density or h/o
osteoporotic fracture)
• 734 patient per arm randomized to placebo or denosumab 60 mg sq q 6 mos
Smith MR et al, NEJM, 2009.

32. Combining castration therapy with other treatments in
castration-sensitive prostate cancer
• ADT – until June 2014 was the standard of care for all patients
with metastatic castration-sensitive prostate cancer
• Earlier study with docetaxel failed to show significant survival
benefit for patients with castration-sensitive metastatic
prostate cancer – most with “low volume” disease (Gravis G, et al.
(2013) The Lancet Oncology; 14:149-58.)
• Data in support of combining ADT with 6 cycles of docetaxel +
prednisone presented at ASCO Annual Meeting 2014:
ChemoHormonal Therapy Versus Androgen Ablation
Randomized Trial for Extensive Disease in Prostate Cancer
(CHAARTED)

33. Castration-sensitive metastatic prostate cancer:
CHAARTED study comparing ADT to ADT + docetaxel (D)
with prednisone
• 1:1 randomization to ADT alone or ADT + D dosed
75mg/m2 every 3 weeks for 6 cycles within 4 month of
starting ADT
• Primary Endpoint: Overall Survival
• 790 men: ADT N=393; ADT + D: N=397
• High Volume Disease: 64% on ADT and 67% on ADT + D
• 1 death due to ADT + D, 0 deaths from ADT alone
Sweeney C, et al. (2014) J Clin Oncol 32:5s, (suppl; abstr LBA2).

34. Primary endpoint: Overall survival
Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
Adding docetaxel to ADT improves survival in men with
metastatic castration-sensitive prostate cancer

35. OS by extent of metastatic disease at start of ADT
Presented By Christopher Sweeney at 2014 ASCO Annual Meeting
Adding docetaxel to ADT improves survival in men with
metastatic castration-sensitive prostate cancer

36. Castration-resistant prostate cancer
• Majority of patients with metastatic prostate cancer
experience disease progression within 2-3 years despite
surgical or chemical castration
• CRPC is principally responsible for prostate cancer mortality: <
20% of patients with CRPC survive beyond 3 years
• “Castration resistant” “Androgen independent”

37. Mechanisms of prostate cancer progression and
castration resistance: targets for therapy
• Persistent androgen signaling despite castration therapy
• Microtubule polymerization
• Immune escape
• Interactions with bone microenvironment

38. Hormonal manipulation beyond castration
• Block extra-gonadal androgen production
• Block the androgen receptor

39. Sites of inhibition of androgen biosynthesis and
androgen-mediated signaling
• Castration therapy: depletes the 90-95% of circulating T
produced by testes
• 25% of circulating DHT produced by testes – the more
relevant androgen for mCRPC
• Adrenal glands and prostate cancer cells produce androgens

40. Inhibition of CYP17 (17a-hydroxylase / 17,20-lyase) to
impair androgen synthesis: abiraterone acetate
• Abiraterone acetate: Irreversible inhibitor of CYP17 (17a-hydroxylase /
17,20-lyase)
• Predominant toxicities from mineralocorticoid excess due to loss of
negative feedback on ACTH: hypertension, hypokalemia, edema
• Prednisone 5 mg twice daily co-administered with abiraterone acetate
1000 mg daily to suppress symptoms of secondary hyperaldosteronism
Acquired de novo androgen synthesis by the testis and extra-gonadal sources in mCRPC
Figure from Reid AHM, et al. (2009) Nat Clin Pract Urol;5:610-20

41. Abiraterone acetate improves overall survival (OS) for
men with mCRPC
• I. Post-docetaxel trial: Randomized, placebo-controlled phase III study
compared abiraterone acetate 1000 mg daily + prednisone 5 mg bid to
placebo + prednisone 5 mg bid 2:1 (779 vs 398) for treatment of men with
mCRPC who had received prior docetaxel chemotherapy
• Primary endpoint: OS
• Improved OS of 14.8 vs 10.9 mos (HR 0.65, P < 0.001) with median f/u of
12.8 mos
• II. Pre-docetaxel trial: Randomized, double-blind, phase III study of
abiraterone 1000 mg daily + prednisone 5 mg bid vs placebo + prednisone
in men with metastatic CRPC
• 546 vs 542 subjects
• Co-Primary endpoints:
– Radiographic PFS
– OS
• Median PFS 16.5 vs 8.3 months, HR 0.53, P<0.001
• Median OS 35.3 mos vs 30.1 mos, HR 0.79
de Bono JS, et al. NEJM 2011; 364:1995-2005.
Ryan CJ, et al. NEJM 2013; 368:138-148

42. Hormonal manipulation beyond castration
• Block extra-gonadal androgen production
• Block the androgen receptor

43. Androgen receptor signaling
Friedlander TW and Ryan CJ. Urol Clin N Am 2012; 39:453-464.
The presence of testosterone (T) or dihydrotestosterone (DHT) causes dissociation of HSP, dimerization, and
phosphorylation (P) of the AR and translocation to the nucleus where the AR binds to an ARE,causing
recruitment of DNA transcriptional machinery and gene transcription. (Adapted from Li J, Al-Azzawi F.
Mechanism of androgen receptor action. Maturitas 2009;63:142–8; with permission.)

44. Nonsteroidal AR Antagonists
- Block agonist access to the AR ligand-binding domain
-Three 1st generation anti-androgens used in standard practice
-Bicalutamide > Nilutamide > Flutamide
-All have relatively poor binding affinity for AR compared to
endogenous agonists T and DHT
-Partial agonist activity
-Some patients will temporarily benefit from anti-androgen
withdrawal
-No established overall survival benefit for patients with mCRPC

45. Antagonists of androgen receptor function:
enzalutamide
• Enzalutamide is an AR signaling inhibitor
• Derived from chemical screen targeting AR-overexpressing
prostate cancer model
• Impairs AR nuclear translocation, DNA binding, and co-
activator recruitment
• Increased affinity for AR vs bicalutamide
• Pure AR antagonist
Tran C, et al. Science 2009; 324:787-790
Scher HI, et al. NEJM 2012; 367:1187-1197

46. Antagonists of androgen receptor function:
enzalutamide
• AFFIRM: phase III RCT of men with mCRPC following docetaxel
• Enzalutamide 160 mg daily (800) vs placebo (399)
• Median OS: 18.4 vs 13.6 mos (HR 0.63, P<0.001)
• PREVAIL: phase III study vs placebo in chemotherapy –naïve
patients: OS and rPFS were co-primary endpoints
• 1,717 men were randomized 1:1 to enzalutamide vs placebo
• 81% reduction in rPFS (65% vs 14%, HR 0.19, P<0.001) and
29% reduction in risk of death (72% vs 63% survival, HR 0.71,
95% CI 0.60-0.84, P<0.001) with enzalutamide treatment
Scher HI, et al. NEJM 2012; 367:1187-1197.
Beer TM, et al. NEJM 2014; 371:424-433.

47. Microtubule stabilization as a rational therapeutic
target in prostate cancer
• Prostate cancer cells:
long doubling times, low
fraction of dividing cells
– is chemotherapy
relevant?
• Microtubules: dynamic
polymers of a- and b-
tubulin heterodimers
• Essential for regulation
of chromosomal
segregation
• Role in AR nuclear
translocation
• Inhibition can increase
nuclear accumulation of
AR-suppressor FOXO1
• Inhibition by taxanes can
decrease AR expression
Mistry SJ and WK Oh. (2013) Mol Cancer Ther; 12:555-66.

48. Microtubule stabilizers: docetaxel
• TAX 327: Phase III study of 1006 men with mCRPC received prednisone 5
mg bid and randomized to docetaxel 75 mg/m2 q 3 weeks vs 30 mg/m2
weekly for 5/6 weeks vs mitoxantrone 12 mg/m2 q 3 weeks
• Medians OS: 18.9 mos vs 17.4 mos vs 16.5 mos (HRf 0.76, p = 0.009 for q 3
week docetaxel)
• Increased PSA response rate, decreased pain, and improved QoL with
docetaxel
• SWOG 99-16: Phase III study of men randomized to 21-day cycles of 280
mg estramustine (estradiol-linked nitrogen-mustard) tid days 1-5 and 60
mg/m2 docetaxel on day 2 and 60 mg dexamethasone in 3 divided doses
pre-docetaxel vs. mitoxantrone 12 mg/m2 day 1 plus prednisone 5 mg bid
• Median OS 17.5 vs 15.6 mos, HR 0.80, P=0.02
• Improved median TTP and PSA response rate with docetaxel
Tannock IF et al., NEJM 2004; 351:1502.

49. Microtubule stabilizers: cabazitaxel
• Cabazitaxel: docetaxel derivative with decreased affinity for P-glycoprotein
efflux pump and improved ability to cross blood-brain barrier
• TROPIC phase III study: 755 men with mCRPC following docetaxel
treatment treated with prednisone 10 mg daily and randomized to 25
mg/m2 cabazitaxel q 3 weeks vs mitoxantrone 12 mg/m2 q 3 weeks
• Median OS: 15.1 mos vs 12.7 mos, HR 0.70 (95% CI 0.59-0.83, p<0.001)
• 82% in cabazitaxel group with grade > 3 neutropenia, 6% grade > 3
diarrhea, 8% febrile neutropenia
• Growth factor support required
• FDA mandated non-inferiority study of 20 mg/m2 vs 25 mg/m2
• FDA mandated 20 mg/m2 or 25 mg/m2 vs docetaxel
de Bono JS, et al. Lancet 2010; 376:1147

50. Immunotherapy for CRPC
• Immune escape is a hallmark of
cancer
• Increased activity of
immunosuppressive T regulatory
cells (Treg), myeloid-derived
suppressor cells (MDSC)
• Upregulation of T-cell inhibitory
checkpoint pathways (CTLA-4,
PD-1)
• Impaired tumor antigen
presentation by antigen
presenting cells (APCs)
• Prostate-cancer specific antigens
are non-essential: attractive
therapeutic targets
Sipuleucel-T
Prostate cancer
cell
PSA PAP
T cell
Dendritic
cell
CTLA-4

51. Sipuleucel-T for metastatic CRPC
• Active cellular immunotherapy approved for treatment of
asymptomatic or minimally symptomatic men with mCRPC
• CD45+ APCs collected by leukapheresis and pulsed with fusion
construct of prostatic acid phosphatase (PAP) and
granulocyte-macrophage colony-stimulating factor (GM-CSF)
called PA2024
• 3 leukapheresis procedures each separated by 2 weeks, with
reinfusion of sipuleucel-T 3 days after each leukapheresis
Sonpadve G and Kantoff PW. Urol Clin N Am 2012; 39:465-481.
Kantoff PW, et al. NEJM 2010; 363:411-422.

52. Sipuleucel-T for metastatic CRPC
• Two “identically designed” phase III, double-blind, placebo-
controlled trials (D9901, D9902A) of 225 patients (147 sipuleucel-T
vs 78 placebo) failed to demonstrate improvement in the primary
endpoint (TTP), but showed apparent improvement (D9901) and
trend toward improvement (D9902A) in median OS
• IMPACT: phase III trial of men with asymptomatic or minimally
symptomatic metastatic CRPC with primary endpoint of OS
• Randomized 2:1 (n = 512) to sipuleucel-T vs APCs not pulsed with
PA2024
• Improved median OS 25.8 vs 21.7 mos, HR 0.77; P = 0.2
• No delay in first TTP
• Few PSA declines or objective responses
Small EJ, et al. JCO 2006; 24:3089-3094
Higano CS, et al. Cancer 2009; 115:3670-3679
Kantoff PW, et al. NEJM 2010; 363:411-422

53. Promising immunotherapies under investigation
• Phase III study of ipilimumab (anti-
CTLA-4) in men with previously
treated CRPC showed no
improvement in OS, but improved
PFS; ongoing study in
chemotherapy-naïve patients
• Ongoing PROSTVAC-VF TRICOM
phase III study: poxvirus-based
vaccine therapy where
recombinant vaccinia and fowlpox
vectors express PSA and
costimulatory molecules (TRICOM)
Sonpadve G and Kantoff PW. Urol Clin N Am 2012; 39:465-81.
Suzman DL and Antonarakis ES. Ther Adv Med Oncol 2014; 6:167-79.
Prostate cancer
cell
PSA
T cell
CTLA-4
PROSTVAC-VF TRICOM
Ipilimumab

54. Prostate cancer bone tropism and bone-targeted
therapies
• ~ 90% of patients with metastatic
prostate cancer develop bone
metastases
• Zoldedronic acid (bisphosphonate)
and denosumab (RANKL inhibitor)
approved in mCRPC to reduce SREs
• Strontium-89 and samarium-153
lexidronam (beta-emitters) approved
to provide palliation for painful bone
metastases
Pal SK, Lewis B, and Sartor O. (2012) Urol Clin N Am; 39:583-91.
Keller ET, et al. (2001) Cancer Metast Rev; 333-49.
Model of cross-talk between
prostate cancer and bone
microenvironment: a “vicious
cycle” where CaP cells stimulate
osteoclasts to break down bone,
releasing growth factors that
support proliferation of CaP, which
releases factors supporting
osteoblast proliferation/survival.

55. Radium-223 dichloride preferentially targets osteoblastic
metastases
• Bone-targeted a-emitter
• Effective at inducing DNA double-strand breaks
• Emission over a short (microns) path-length vs. b-radiation (millimeters)
• Calcium mimic with preferential uptake in osteoblastic metastases vs. normal bone
Imaging Radium-223
Cheetham PJ and DP Petrylak (2012) Oncology; epub.
Pandit-Taskar N, et al. (2014) J Nucl Med; 55:268-74.

56. Bone-targeted therapies: radium-223 chloride
• ALSYMPCA:
• Randomized phase III study of patients with mCRPC
previously treated with, unfit for, or refusing docetaxel
• Symptomatic CRPC with > 2 bone lesions with no visceral
metastases or bulky (>3 cm) lymph nodes
• 921 patients randomized 2:1 to Ra-223 vs placebo
• 6 injections 50 kBq/kg IV q 4 wks vs placebo
• Median OS: 14.9 vs 11.3 mos, HR 0.70, 95% CI 0.58-0.83,
P<0.001
• Prolonged time to 1st SRE: 15.6 vs 9.8 mos, HR 0.66, 95% CI
0.52-0.83, P<0.001
• Low rates of Ra-223-associated myelosuppression
Parker C, et al. NEJM 2013; 369:213-223.

57. Agent Action Year Primary Endpoint
Estramustine Nitrogen mustard-estradiol conjugate 1981 Disease responses
Strontium-89 Radiopharmaceutical 1993 Pain palliation
Mitoxantrone + prednisone Type II topoisomerase inhibitor 1996 Pain palliation
Samarium-153 Radiopharmceutical 1997 Pain palliation
Zoledronic acid Bisphosphonate 2002 Reduced SRE
Docetaxel + prednisone Microtubule stabilizer 2004 Overall Survival
Sipuleucel-T Cell-based immunotherapy 2010 Overall Survival
Cabazitaxel + prednisone Microtubule stabilizer 2010 Overall Survival
Denosumab mAb to RANKL 2010 Reduced SRE
Abiraterone + prednisone CYP17 inhibitor 2011, 2012* Overall Survival
Enzalutamide AR antagonist 2012, 2014* Overall Survival
Radium-223 Radiopharmaceutical 2013 Overall Survival
Currently approved therapies for metastatic CRPC
SRE, skeletal-related event; mAb, monoclonal antibody; RANKL, receptor of nuclear factor kappa-B ligand; * dates are for FDA
approval for treatment of patients post- and pre-docetaxel, respectively
Modified from Pal SK, Lewis B, and Sartor O. Urol Clin N Am 2012; 39:583-591.

58. Mechanisms of resistance to current therapies:
potential therapeutic targets?
• AR mutations, overexpression, and splice variants
• Glucocorticoid receptor (GR) upregulation
• 3bHSD mutation
• Alternative signaling pathways (eg: PI3K / AR crosstalk;
Met/VEGFR)

59. Areas of ongoing investigation
• Optimal sequencing of available therapies?
• Combination therapies?
• Earlier interventions targeting potential future mechanisms of
resistance?

60. My approach to treatment of metastatic prostatic
adenocarcinoma
 Castration-sensitive:
 Start with GnRH-agonist or antagonist (orchiectomy or ketoconazole +
hydrocortisone if emergent castration required) if low-volume disease and discuss
findings of CHAARTED study
 Start with ADT + 6 cycles of docetaxel w/prednisone if high-volume disease
 Castration-resistant:
 Sipuleucel-T if asymptomatic / minimally symptomatic: monitor clinical and
radiographic response (pre- or post-docetaxel, but appears to be of greatest
efficacy early
 Abiraterone plus prednisone (pre- or post-docetaxel)
 Enzalutamide (pre- or post-docetaxel)
 Radium-223 if symptomatic bone-only metastatic disease (pre- or post-docetaxel)
 Docetaxel plus prednisone (earlier if symptomatic)
 Cabazitaxel plus prednisone with growth factor support
 Clinical trials warrant consideration at any point from time of diagnosis

61. Germ Cell Tumors (Testicular
Cancer)
Acknowledgement: Christopher Sweeney, MBBS,
Associate Professor of Medicine, Harvard Medical
School ,
Clinical Director, The Lank Center for Genitourinary
Oncology, Dana-Farber Cancer Institute

62. Testicular Cancer: Incidence and Mortality
• American Cancer Society 2015 US estimates:
• 8,430 new cases of testis cancer
• 380 testis cancer deaths
• > 90% of patients with germ cell tumors are cured
• 70-80% of patients with advanced tumors treated with
chemotherapy are cured
Siegel RL, et al. “Cancer Statistics, 2015.” CA: A Cancer Journal for Clinicians (2015) 65:5-29.

63. Germ cell tumors
• Seminomas
• Non-seminomatous germ cell tumors (NSGCT)
• Treat mixed seminoma + NSGCT as NSGCT
• Children: NSGCT > seminoma
• Adults: Seminoma > NSGCT
• Most commonly diagnosed ages 15-40

64. GCT sites of origin
• Gonads (testicles, ovaries)
• Pineal gland
• Anterior mediastinum
• Midline retroperitoneum
• Rare sites (liver, sacrum, paranasal sinuses)

65. Seminoma
• Tumor markers:
– Can make beta human chorionic gonadotropin (bHCG) and lactate
dehydrogenase (LDH)
– Cannot make alpha-fetoprotein (AFP)
• No teratoma component
• Significant role for radiation
• Less role for surgery than NSGCT

66. NSGCT
• Histologies
– Embryonal carcinoma
– Yolk sac tumor
– Teratoma
• Chemotherapy insensitive (surgery)
• Mature or immature
• Can de-differentiate (sarcoma, carcinomas)
– Choriocarcinoma
– Seminoma
• Tumor markers
– can make AFP, LDH, and bHCG (or none)

67. Seminoma vs NSGCT
Seminoma
• More likely to be localized
at presentation
• Very radiosensitive
• Tumor markers less useful
• More indolent and longer
natural history
– Longer median time to
relapse
– More common late relapses
NSGCT
• More likely to have
metastasized at
presentation
• Not radiosensitive
• Tumor markers useful
indicator of viable tumor
• More likely hematogenous
spread

68. Risk factors
• Cryptorchidism
• History of GCT
• Intratubular germ cell neoplasia
• Family history – specific genetic factors unknown
• HIV infection – much higher risk for seminoma
• Klinefelter syndrome (mediastinal GCT)
• Down syndrome
• Androgen insensitivity syndromes and mixed gonadal
dysgenesis

69. Patterns of GCT lymphatic spread
• Primary drainage of testis: to embryological origin in the
retroperitoneum
• Tumors of right testicle
– Interaortocaval lymph nodes
– Precaval and preaortic lymph nodes
– Contralateral spread more common
• Tumors of left testicle
– Para-aortic and pre-aoritc nodes
– Interaortocaval nodes
• Aberrant spread: cryptorchidism, inguinal surgery, biopsy

70. Tumor markers
• AFP
– T1/2 5 days if no cancer post-orchiectomy
– Log reduction after each cycle of chemotherapy
– False +: liver, familial
• bHCG
– T1/2 24 hours if no cancer post-orchiectomy
– Log reduction after each cycle of chemotherapy
– False +: LH (cross reacts), marijuana, pituitary secretion
• LDH
– Multiple enzymes
– Correlates with tumor burden / proliferation rate
– Other causes (non-specific)

71. Work up of suspicious testicular mass
• H&P: painless solid testicular mass is pathognomomic
• Labs: Tumor markers (AFP, bHCG, LDH), chemistry
profile
• CXR
• Testicular ultrasound
• Discuss sperm banking
• Radical inguinal orchiectomy
• Consider inguinal biopsy if
– Suspicious US for intratesticular abnormalities
– Cryptorchid testis
– Marked atrophy

72. Post-orchiectomy workup
• CT abdomen/pelvis
• CT chest if + CT A/P or abnormal CXR
• Repeat tumor markers (TNM staging based on post-
orchiectomy values)
• Brain MRI if clinically indicated
• Bone scan if clinically indicated
• Discuss sperm banking
• PFTs if BEP chemotherapy planned

73. Risk classification for advanced germ cell
tumors
Seminoma
• Good risk: any primary site,
no non-pulmonary visceral
metastases, any bHCG or
LDH
• Intermediate risk: non-
pulmonary visceral
metastases
NSGCT
• Good risk: testicular or
retroperitoneal primary, no
non-pulmonary visceral
mets, and low tumor
marker levels
• Intermediate risk: same as
good risk but intermediate
tumor marker levels
• High risk: mediastinal
primary or non-pulmonary
visceral mets or high tumor
marker levels

74. Primary chemotherapy regimens for
germ cell tumors
• EP: etoposide, cisplatin
• BEP: bleomycin, etoposide, cisplatin
• VIP: etoposide, ifosfamide, cisplatin (for
patients with poor risk NSGCT)

75. Treatment: seminoma stage I (localized disease)
• Stage IA (pT1N0M0S0), IB (pT2-4N0M0S0)
– Surveillance (pT1-pT3) or
– Carboplatin x 1 or 2 cycles or
– Radiation therapy
• Stage IS (no mets, persistent + markers)
– Radiation therapy

76. Treatment: seminoma stage II (regional lymph
node involvement)
• Stage IIA
– RT (preferred) or Chemotherapy for multiple + LNs
(BEP x 3, EP x 4)
• Stage IIB
– Chemotherapy (preferred; BEP x 3, EP x 4) or RT in
select non-bulky cases
• Stage IIC - chemotherapy
– Good risk: BEP x 3 or EP x 4
– Intermediate risk: BEP x 4

77. Treatment: seminoma stage III – distant
metastasis
• Stage III – chemotherapy
– Good risk: BEP x 3 or EP x 4
– Intermediate risk: BEP x 4

78. Treatment: localized NSGCT
• Stage IA
– Surveillance or
– Nerve-sparing RPLND
• Stage IB
– Nerve-sparing RPLND or
– Chemotherapy (BEP x 1 or 2 cycles) or
– Surveillance (T2 only)
• Stage IS
– Chemotherapy (BEP x 3 or EP x 4)

79. Treatment of metastatic NSGCT: risk-
stratification more relevant than stage*
• Stage IIA
– Negative tumor markers: RPLND or BEP x 3 or EP x 4
– Positive tumor markers: chemotherapy*
• Stage IIB
– Negative markers: BEP x 3 or EP x 4 or RPLND
– Positive tumor markers: chemotherapy
• Stage IIC, IIIA, IIIB, IIIC
– Chemotherapy* (EP x 3 or BEP x 4 or VIP x4
depending on both disease risk and disease stage)

80. Second line chemotherapy regimens
for germ cell tumors
• VeIP: vinblastine, ifosfamide, cisplatin
• TIP: paclitaxel, ifosfamide, cisplatin
• High-dose chemotherapy regimens (prior to
autologous stem cell transplants)
• Palliative chemotherapy regimens
– Gemcitabine/oxaliplatin
– Gemcitabine/paclitaxel
– Gemcitabine/paclitaxel/oxaliplatin
– etoposide

81. Treatment-associated toxicities
• Neurotoxicity: ototoxicity, peripheral neuropathy
• Nephrotoxicity: cisplatin
• Pulmonary toxicity: bleomycin, cisplatin
• Infertility
• Hypogonadism
• Raynaud’s syndrome
• Cardiovascular disease: cisplatin, RT
• Secondary leukemia (cisplatin, etoposide)