mCRPC Presentation

E. David Crawford, MDProfessor of Surgery/Urology/Radiation Oncology

E. David Crawford DistinguishedEndowed Chair in Urology

Head Urologic OncologyUniversity of Colorado, Denver

2018

E. David CrawfordUC School of Medicine

Outline• Intro/background• nmCRPC• Resistance to hormonal therapy• Alternative approved treatments• Moving on in the new era– Combinations– Biomarkers– NEPC / t-NEPC / t-SCNC– Additional targets

Historical Developments in Prostate Cancer

1904First radical prostatectomy

1940Huggins -endocrine control, use of orchiectomy, and estrogen treatment (Awarded Nobel Prize)

1970sSteroidal and non-steroidal antiandrogens available1970sSchally and Guillemin-LHRH discovery (Awarded Nobel Prize)

1980sLong-acting synthetic LHRH agonists

2003First GnRH antagonist (abarelix)

The future…New androgen receptor-targeted drugs, vaccines, biomarkers, genetic research

1867First perinealprostatectomy

2008Degarelix approved

1780CastrationJohn Hunter

1970sDiscovery and characterization of androgen receptor

1995Bicalutamide available

2018 Apalutamide approved in nmCRPC

1900 1940 1970 1980 2000 2020

2011Abiraterone approved

1990 2010

2012 Second-generationantiandrogen approved (enzalutamide)

SOURCE: Dr. ED Crawford

1938Acid Phosphatase

Therefore, targeting the AR by reducing serum T to castrate levels via ADT has become standard of care for patients with advanced prostate cancer

Sources of Androgen Production

Androgens are produced at 3 sites

Prostate tumor cells

TestesAdrenal

glands

Reducing availability of androgen (T) to bind and activate the AR (lowering androgen levels or blocking receptor) decreases tumor cell proliferation

Activation of the AR signaling pathway by androgen is critical for prostate cancer tumor growth and diseaseprogression

Potential Adverse Events Associated with ADT

QOL ISSUES MEDICAL ISSUES

• Osteoporosis/skeletal events

• DiabetesNeurocognitive

disease • Anemia• Gynecomastia

• Thinning of body hair

• Testicular atrophy

• Cardiovascular disease

• Hot flashes• Loss of libido• Erectile dysfunction• Fatigue

.

Management of Prostate Cancer

Crawford 2018

• Which drug for which patient?– Options but no specifications– No comparative data

• What is the best sequence?– Only docetaxel studies

• When to stop a drug therapy?– Guidelines tell us when to start, not stop

• Is combination therapy appropriate?– It is a paradigm used in other cancers

What the Guidelines Do NOT Tell Us

CRPC TREATMENT EVOLUTION2004:

DocetaxelTannock et al.

(TAX 327)

2010: Cabazitaxel

de Bono et al.(TROPIC)

2010: Sipuleucel-T Kantoff et al.

(IMPACT)

2011: Abiraterone

de Bono et al.(COU-AA-301)

2012: Enzalutamide

Scher et al.(AFFIRM)

2013: AbirateroneRyan et al.

(COU-AA-302)

2005 2007 2009 2011 2013

2013:Radium 223Parker et al.(ALSYMPCA)

2014

2014: Enzalutamide

Beer et al.(PREVAIL)

While the greater availability of treatment agents benefits patients, the multiple options and sequencing of medications complicates clinical decision-making.

2018

ApalutamideSmall, et. al(SPARTAN)

EnzalutamideHussain, et. al (PROSPER)

Goals of Therapy in CRPC

• LifePROLONG

• Pain• Complications (e.g. skeletal events)• Decline in performance status

PREVENT

• Quality of life• Performance statusPRESERVE

INDEX PATIENT 1 (2017)

Asymptomatic non-metastatic CRPC (M0)

Clinicians should recommend observation with continued androgen deprivation to patients with non-metastatic CRPC. (Recommendation; Evidence Level Grade C)

Clinicians may offer treatment with first- generation anti-androgens (flutamide, bicalutamide and nilutamide) or first-generation androgen synthesis inhibitors (ketoconazole+steroid) to select patients who are unwilling to accept observation. (Option; Evidence Level Grade C)

Clinicians should NOT offer systemic chemotherapy or immunotherapy to patients with outside the context of a clinical trial. (Recommendation; Evidence Level Grade C)

No evidence of metastasis

DEFINING CRPC IN 3 STEPS

12

Rising PSA while on ADT

Serum testosterone levels below

50 ng/dL

nmCRPC

mCRPC=metastatic CRPC; nmCRPC=nonmetastatic CRPC.Cookson MS, et al; American Urological Association. J Urol. 2015;193(2):491-499.

Evidence of metastasis

mCRPC

nmCRPC IS DEFINED BY BIOCHEMICAL PROGRESSION ONLY—WITH NO RADIOGRAPHIC PROGRESSION*

13

EAU/ESTRO/SIOG1Three consecutive rises of PSA, 1 week apart, resulting in two 50% increases over the nadir, and PSA >2 ng/mL

Appearance of new lesions:• ≥2 new bone lesions on bone scan, or• A soft tissue lesion using Response

Criteria in Solid Tumors (RECIST)

PCWG22

A rising PSA of ≥25% and absolute increase of ≥2 ng/mL from the nadir, confirmed by a second value obtained ≥3 weeks later

• ≥2 new lesions on bone scan, or• Progression in nodal or visceral site

using RECIST

CRPC is defined by 1 or more of the following types of disease progression despite castrate levels of serum testosterone (<50 ng/dL or <1.7 nmol/L)

Biochemical progression Radiologic progression

nmCRPC is defined by evidence of biochemical progression with noradiologic evidence of metastatic disease3

Of note, health care professionals should engage in shared decision-making with patients regarding follow-up intensity.EAU = European Association of Urology; ESTRO = European Society for Radiotherapy & Oncology; PCWG2 = Prostate Cancer Clinical Trials Working Group; SIOG = International Society of Geriatric Oncology. *Radiographic progression indicates mCRPC.

1. Cornford P, et al. Eur Urol. 2017;71(4):630-642. 2. Scher HI, et al. J Clin Oncol. 2008;26(7):1148-1159. 3. Cookson MS, et al; American Urological Association. J Urol. 2015;193(2):491-499.

PSADT CAN HELP RISK STRATIFY PATIENTS WITH

nmCRPC1-3

Faster PSADT is linked to shorter time to metastasis in patients with nmCRPC2*

*PSADT calculated by log(2) divided by the slope of the linear regression of log(PSA) over time in months. Study included data from 441 men with M0 CRPC at 5 Veterans Affairs Medical Centers obtained from the SEARCH database. †Retrospective cohort study of 9547 patients from the Center for Prostate Disease Research database. 1. Moreira DM, et al. Urology. 2016;96:171-176. 2. Howard LE, et al. [published online March 28, 2017]. BJU Int. doi:10.1111/bju.13856. 3. Metwalli AR, et al. Urol Oncol. 2014;32(6):761-768.

PSADT (months) Median Time to Metastasis (months)

<3 9

3 to 8.9 19

9 to 14.9 40

≥15 50

Howard LE, et al. [published online March 28, 2017]. BJU Int. doi:10.1111/bju.13856, with permission from John Wiley & Sons.

Patients with PSADT <10 months had 12 times greater risk of bone metastasis

and 4 times greater risk of death than those with PSADT ≥10 months3†

Howard LE, et al. [published online March 28, 2017]. BJU Int. doi:10.1111/bju.13856, with permission from John Wiley & Sons.

*PSADT calculated by log(2) divided by the slope of the linear regression of log(PSA) over time in months. Study included data from 441 men with M0 CRPC at

5 Veterans Affairs Medical Centers obtained from the SEARCH database. †Retrospective cohort study of 9547 patients from the Center for Prostate Disease

Research database. 1. Moreira DM, et al. Urology. 2016;96:171-176. 2. Howard LE, et al. [published online March 28, 2017]. BJU Int. doi:10.1111/bju.13856.

3. Metwalli AR, et al. Urol Oncol. 2014;32(6):761-768.

PSADT predicts bone mets or death

• Men with nmCRPC with a prostate-specific antigen doubling time (PSADT) of < 8-10 months are at significant risk for metastatic disease and prostate cancer–specific death1

1. Smith MR, et al. J Clin Oncol. 2013;31:3800-3806.

PSADT (Months)

Rel

ativ

e R

isk

for B

one

Met

asta

sis

or D

eath

Shorter PSADT

Incr

easin

g Ri

sk

20 18 16 14 12 10 8 6 4 2

3.02.8

2.6

2.4

2.2

2.0

1.81.6

1.4

Future Directions: M0 CRPC

Many clinical trials are now completing/completed

Newer Therapies: Androgen Pathway Inhibitors

• 1st generation ADT drugs (antiandrogens) target the AR

• 2nd generation ADT drugs (LHRH agonists/antagonists) target LHRH receptors

• 3rd generation drugs have additional mechanisms and are described as

androgen pathway inhibitors (APIs)

• APIs further reduce activation of AR beyond ADT:

– Reduce T levels to almost zero (eg. abiraterone)

– More effectively block AR signaling (eg.

enzalutamide)

• All APIs require concomitant ADT

• APIs initially approved for mCRPC, now also approved in mCSPC and nmCRPC

• Efficacy of APIs demonstrates importance of androgen signaling pathway

across disease continuum

ANDROGEN TARGETED THERAPY ACROSS THE CONTINUUM OF PROSTATE CANCER 18

Abiraterone Acetate

• Abiraterone inhibits 17 α-hydroxylase/C17,20-lyase (CYP17) � CYP17 involved in androgen biosynthesis� CYP17 is expressed in testicular, adrenal, and prostatic tumor

tissues• First approved in 2011 for mCRPC• Now approved in 2018 for mCSPC• Concomitant use with prednisone to prevent excess

mineralocorticoid effects• Food effect requires dosing 1 hour before or

2 hours after a meal

Abiraterone Efficacy mCRPCCOU-AA-302 Trial (pre-chemotherapy)Patients with metastatic CRPCwho had not received prior chemotherapy

COU-AA-301 Trial (post-chemotherapy)Patients with metastatic CRPC who had received prior chemotherapy

Median survival (months) 15.8 v 11.2 (placebo)Hazard ratio 0.740

Median survival (months) 34.7 v 30.3 (placebo)Hazard ratio 0.81

% S

urvi

val

Months from Randomization

100

80

60

40

20

00 3 6 27 36 45 51 579 12 15 18 21 24 30 33 39 42 48 54 60

Kaplan Meier Overall Survival Curves in COU-AA-302

PlaceboAbiraterone

Kaplan-Meier Overall Survival Curves in COU-AA-301

PlaceboZytiga

% S

urvi

val

100

80

60

40

20

00 3 6 9 12 15 18 21

Time to death, months

PlaceboAbiraterone

Abiraterone in mCSPC/Newly Diagnosed Metastatic DiseaseLATITUDE Trial• Improved overall survival by 38% (shown)

• Improved PFS by 53%

• Improved PSA progression by 70%

• Improved symptomatic skeletal events by 30%

STAMPEDE Trial• Improved overall survival by 37% (shown)

• Improved failure free survival by 71%

• Improved symptomatic skeletal events by 55%

HR 0.6395% CI 0.52 to 0.76

P-value 0.00000115

OS – All Patients

HR 0.6295% CI 0.51–0.76

P-value < 0.001

OS

Potential Side Effects of Abiraterone

FatigueArthralgiaHypertensionNauseaEdemaHypokalemiaFluid retentionHot flushDiarrhea

VomitingURTICough and HeadacheAdrenocortical insufficiency Hepatotoxicity

Some events relate to concurrent use of prednisone

ANDROGEN TARGETED THERAPY ACROSS THE CONTINUUM OF PROSTATE CANCER 22

Enzalutamide

•Enzalutamide is a 3rd generation AR inhibitor •Has activity at 3 places •Blocks binding of androgen to AR•Prevents AR from entering cell nucleus• Inhibits AR binding to DNA

•First approved in 2012 for mCRPC•Now approved in 2018 for nmCRPC

Enzalutamide Efficacy in mCRPC

Prevail Trial (pre-chemotherapy)• PFS at 12m: 65% for enzalutamide v

14% placebo (81% risk reduction; HR

0.19; P<0.001)

• 29% reduction in risk of death; HR

0.71; P<0.001

Affirm Trial (post-chemotherapy)• OS 18.4m for enzalutamide group versus

13.6m placebo group

• HR for death in enzalutamide group, 0.63

• time to PSA progression: 8.3m enzalutamide

v 3.0m placebo, HR 0.25; P<0.001

Potential Side Effects of Enzalutamide

SeizuresFatigueBack painDecreased appetiteGI disorders, arthralgiaHot flashesURTI

EdemaDyspneaMusculoskeletal painWeight lossHeadacheHypertensionDizziness

Ischemic heart diseaseFallsPosterior reversible encephalopathy syndrome

ANDROGEN TARGETED THERAPY ACROSS THE CONTINUUM OF PROSTATE CANCER 25

Apalutamide

•Apalutamide is a 3rd generation AR inhibitor that binds directly to the ligand-binding domain of the AR •First approved in 2018 for nmCRPC

PROSPER Trial (enzalutamide)•median metastasis-free survival was 36.6m for

enzalutamide v 14.7m for placebo group (HR for metastasis or death, 0.29; P<0.001• time to PSA progression (37.2m for

enzalutamide v 3.9m for placebo; hazard ratio, 0.07; P<0.001; progression occurred in 22% v 69% of patients)

Apalutamide and Enzalutamide in nmCRPC

Met

asta

sis-F

ree

Prob

abili

ty (%

)

Months from Randomization

SPARTAN Trial (apalutamide)• 40.5m v 16.2m for metastasis free survival• 40.5m v 16.6m to metastasis• 40.5m v 14.7m progression free survival• HR 0.28

Potential Side Effects of Apalutamide

FatigueHypertensionRashHypothyroidismDiarrheaNauseaWeight loss

ArthralgiaFalls and fracturesHot flushDecreased appetitePeripheral edemaSeizures

API Conclusions

• Be observant of additional side effects– Hepatotoxicity– Falls/fractures– Seizures

• Identify drug resistance (ARV-7)• Personalize therapy for each

patient– Selection of initial API – Modify if necessary

• Near complete inhibition of AR activation with APIs produces survival benefit in patients with CRPC and CSPC

• Continue effective ADT

• Additional efficacy seen with APIs reinforces importance of achieving lowest T by ADT alone– Lower nadir T in 1st year correlates with

longer time to CRPC and longer CSS

– Patients with higher baseline T derived greater clinical benefit

FACT-P, Functional Assessment of Cancer Therapy–Prostate; HRQoL, health-related quality of life; QoL, quality of life; SD, standard deviation; W, week.

1. Saad F, et al. Poster presented at EAU 2018. abstract 7432. Tombal B, et al. Poster presented at EAU 2018. abstract 605

Effect of treatment on QoL: FACT-PSPARTAN1 PROSPER2

Caveat: Comparing across studies is problematic. This is not a head to head comparison.

The IMAAGEN Study: Effect of Abiraterone Acetate andPrednisone on Prostate Specific Antigen and RadiographicDisease Progression in Patients with Nonmetastatic CastrationResistant Prostate Cancer

Charles J. Ryan,*,† E. David Crawford,† Neal D. Shore,† Willie Underwood III,Mary-Ellen Taplin,† Anil Londhe, Peter St. John Francis,† Jennifer Phillips,†Tracy McGowan† and Philip W. Kantoff

Results: Of the 131 enrolled patients 44 (34%) remained on treatment with a median followup of 40.0 months. Median age was 72 years (range 48 to 90). Of the patients 82.4% were white and 14.5% were black. Median screening prostate specific antigen was11.9 ng/dl and median prostate specific antigen doubling time was 3.4 months. Prostate specific antigen was significantly reduced (p<0.0001) with a 50% or greater prostate specific antigen reduction in 86.9% of cases and a 90% or greater reduction in 59.8%. Median time to prostate specific antigen progression was 28.7 months (95% CI 21.2e38.2). Median time to radiographic evidence of disease progression was not reached but on sensitivity analysis in 15 patients it was estimated to be 41.4 months (95% CI 27.6enot estimable). Baseline testosterone 12.5 ng/dl or greater and a 90% or greater prostate specific antigen reduction at cycle 3 wereassociated with longer time to prostate specific antigen progression and radiographic evidence of disease progression. Outcomes in black patients were similar to those in other patients. Adverse events, grade 3 or greater adverse events and serious adverse events were reported in 96.2%, 61.1% and 43.5% of patients, respectively.Conclusions: In patients with high risk, nonmetastatic, castration resistant prostate cancer treatment withabiraterone acetate plus prednisone demonstrated a significant 50% or greater prostate specific antigenreduction with encouraging results for the secondary end points, including the safety of 5 mg prednisone.

Journal of Urology August 2018

References:1. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. Published online February 8, 2018. doi:

10.1056/NEJMoa1715546.2. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo-controlled study of enzalutamide in men with nonmetastatic, castration-

resistant prostate cancer. Poster presented at: ASCO Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, CA.

31

Apalutamide and enzalutamide extended nmCRPC patients’ median time to metastasis by roughly 2 years compared to placebo.1,2 This prolonged exposure to novel antihormonal agents prior to metastases adds complexity to the selection of initial and subsequent therapies for treating mCRPC when patients do develop metastatic disease

AA

Antiandrogen Monotherapy

AA

DHTT

AA

AA

AA

AA

DHT

DHT

AA AA

DHT

T

— Testosterone

— Dihydrotestosterone

— Antiandrogen

— Androgen Receptor

DHT

T

Antiandrogen

Androgen Receptor

Nucleus

AA

SOURCE: Dr. ED Crawford

Side Effects of Anti-Androgen Monotherapy

• Flutamide• Diarrhea, hepatotoxicity (some fatal)

• Nilutamide• Nausea, dark light accommodation, alcohol

intolerance, hepatotoxicity• Bicalutamide

• Nausea, diarrhea, constipation, hepatotoxicity

Gynecomastia

ConclusionsnmCRPC is a heterogeneous disease.

nmCRPC patients with PSADT < 10 months are at high risk of developing metastases or death.

Apalutamide (2/14/18) and Enzalutamide(7/13/18): now FDA-approved standard for nmCRPC pts.

Final analyses pending regarding OS benefit.

Additional trials needed regarding sequencing options additional lines of therapy.

Additional trials needed regarding implications next generation imaging.

Time to hang it up

Prostate Cancer 2018:We have seen translational therapy lead to real, clinically relevant improvements

for patients