Board Review 2017:Prostate Cancer

Dana Rathkopf, MDAssociate Attendingwww.MSKCC.org

The Paradox of Prostate Cancer

• High prevalence in the general population: over diagnosis of clinically insignificant cancers is a concern.

• Can be less lethal to a patient than existing comorbidities but remains the 2nd leading cause of cancer death in men.

• A natural history that can span 10 years or more, for which treatment can often be deferred at diagnosis or relapse.

“Is cure possible when it is necessary?

  Is cure necessary when it is possible?”

Willet Whitmore, Jr., MD     Chief of the Urology Service, 1952 - 1983     Memorial Sloan-Kettering Cancer Center

Cancer Statistics, United States

Most common malignancy in men other than skin cancer: -1 man in 7 will be diagnosed with prostate cancer-66 is median age of diagnosis

Third leading cause of cancer related death in men: -1 man in 39 will die of prostate cancer- 1 man in 6 diagnosed with prostate cancer will die from the disease

Siegal R CA Cancer J Clin 2017

Incidence and Mortality Rates from Prostate Cancer are Declining

Cancer Incidence, Males Cancer Deaths, Males

• 1994: PSA approved by the FDA to aid in cancer detection• 2011: USPSTF recommends against routine PSA screening• 2010-2013: prostate cancer incidence has dropped >10% annually

Siegal R CA Cancer J Clin 2017

Risk Factors and Prevention

Prostate Cancer Risk Factors• Age: Six in 10 cases of prostate cancer are found in men

older than 65 (median age 66).• Ethnicity: African-American men have the highest

incidence of diagnosis and are twice as likely to die of their disease.

• Geography: Most common in North America, northwestern Europe, Australia, and on Caribbean islands.

• Family History: Higher risk is associated with brother > father with prostate cancer (2x), multiple family members with prostate cancer (especially if < 55 at diagnosis).

• Inherited Gene Changes: BRCA2>BRCA1, Lynch Syndrome (HNPCC)

American Cancer Societyhttps://www.cancer.org/cancer/prostate-cancer

Klein, EA JAMA. 2011

Selenium and Vitamin E Prevention Trial(SELECT)

Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men

HR 1.17CI, 1.04-1.36P= .008

Prostate Cancer Prevention Trial (PCPT): 5 alpha reductase inhibitor

• N=18,880• Placebo vs. finasteride• Detected Prostate Cancer

in 18.4% finasteride vs 24.8% placebo; benefit associated entirely with reduced risk of low grade prostate cancer

• Did not protect against high grade prostate cancer (HR 1.17)

• No benefit in OS

Thompson I, NEJM 2003, 2013

15 year OS rate no different between the two

Schrecengost R and Knudsen K, Seminars in Oncology, 2013

Molecular Pathogenesis and Progression

Enzalutamide

Early Detection, Diagnosis and Staging

The ACS, AUA and NCCN recommend that men should first be informed of the risks and potential benefits of screening, then offered PSA and DRE beginning at age 50 years and continuing annually as long as they have a life expectancy > 10 years.

The discussion should take place at age 45 for men at high risk (African Americans, those with a family history) and at age 40 for very high risk men (several first degree relatives).

Screening Recommendations

Screening for Prostate Cancer U. S. Preventive Services Task Force (USPSTF)

http://www.uspreventiveservicestaskforce.org

Does PSA screening reduce prostate cancer mortality?

PLCO: No ERSPC: Yes

n=76,693

n=182,160HR= 0.895% CI, 0.65-0.98P=0.04

To prevent one prostate-cancer death, 1410 men screened, 48 treated.

Prostate Cancer Pathology

The five-year biochemical recurrence-free progression probabilities for radical prostatectomy Grade Groups 1-5 were 96%, 88%, 63%, 48%, and 26%.

Epstein JI, A contemporary prostate cancer grading system: A validated alternative to the Gleason score. Eur Urol (2016).

Grade Groups

Prostate Cancer Staging

HORMONE-SENSITIVEDiagnosis161, 360

CASTRATION -RESISTANTDeaths From Disease

26, 730

Prostate Cancer Clinical States

ClinicallyLocalizedDisease

Docetaxel2004

Sipuleucel -T2010

Cabazitaxel2010

Abiraterone2011

Enzalutamide2012

Abiraterone2012

Alpharadin2013

Enzalutamide2014

Docetaxel2015

Active Surveillance

Surgery

Radiation +/- ADT

Olaparib2016

BiochemicalRecurrence

(PSA)Metastatic Non-

Metastatic

MetastaticFirst-Line

Treatment

MetastaticPost-Chemo

Intermittent

ADT

Continuous ADT

Treatment of Localized Disease

Primary Androgen Deprivation Therapy (PADT)

• Not recommended. – PADT should not be used as monotherapy in clinically

localized prostate cancer – NCCN 2016• Potosky JCO 2014

– 15,170 pt’s on cancer registries– No survival advantage for PADT

• Lu, JAMA Int Med 2014– 66,717 Medicare– No OS benefit PADT

ADT considerations

• NOT curative• Sexual dysfunction• Obesity• Osteoporosis• DVT• Cognitive effects• Cardiac Risk:

- 5 studies demonstrated increased cardiac side effects of ADT*- Large meta-analysis showed no increased risk (Nguyen JAMA 2011)

*Keating J Clin Oncol. 2006; D’Amico J Clin Oncol. 2007;    D’Amico JAMA. 2008; Saigal CS Cancer. 2008; Tsai HK J Natl Cancer Inst. 2007.

SPCG-4 TrialN = 695

Median of 13.4 years follow-up, most benefit from RP in men < 65 and intermediate risk PC

0.59 (95% CI, 0.45 to 0.79; P<0.0010.75 (95% CI, 0.61 to 0.92; P = 0.007) 0.62 (95% CI, 0.44 to 0.87; P = 0.01)

0.56 (95% CI, 0.41 to 0.77; P = 0.001)*NNT to prevent one death = 8

*Bill-Axelson A N Eng J Med, 2014- Extended follow-up 23.2 years

PIVOT TRIALN=731

Wilt TJ,  et al.,N Engl J Med 2012.

HR 0.6395% CI, 0.36-1.09

P=0.09

HR 0.40; 95% CI, 0.22-0.70; P<0.001

HR 0.8895% CI, 0.71-1.08

P=0.22

Death from Any Cause

Death from Prostate Cancer

Bone Metastases

Radical prostatectomy did not significantly reduce all-cause or prostate cancer specific mortality

Hamdy FC N Engl J Med 2016

ProtecTPSA: 82,429PC: 2664Randomized: 1643 

At a median of 10 years, PCSM was low irrespective of treatment assigned.Surgery and RT associated with lower incidences of disease progression and metastases

• 5 Years: RP 5x > incontinence, RP 2x > erectile dysfunction• Consistent functional decline in both arms after 5 years• 15 years: no significant difference in functional outcomes

Resnick MJ N Engl J Med 2013

Treatment of High-Risk Disease: What is Risk?

Category Definition Surveillance?

Very low  T1c, Gleason score ≤6, PSA < 10, fewer than 3 cores positive, ≤50% involved in each core, PSA density <0.15 ng/mL/g 

Life expectancy: <20 years 

Low  T1-2a, Gleason score ≤6, PSA < 10  <10 years 

Intermediate  T2b-c OR Gleason score 7 OR PSA 10-20  <10 years 

High  T3a OR Gleason score ≥8 OR PSA >20  Not specified

Very high (locally advanced) 

T3b-4  Not specified

Metastatic  Any nodal or distant metastasis 

NCCN 2016

High risk disease: Radiation therapy and ADT

N Patients ADT, months Positive Result (Primary Endpoint)

EORTC 22863(1997, 2010)

412 T3-4, GR 3 WHO 36 vs. 0 OS

RTOG 8531(1997, 2005)

997 T3 or N+ Lifelong vs. 0 OS for Gl 7-10

RTOG 8610 (1995, 2001, 2008)

456 T2-4 or N+ 4 vs. 0 OS did not hit, except low grade disease; DSS

TROG 9601 (2005, 2011)

818 T2b-4; N0 0 vs. 3 vs. 6 OS for 6 mo arm only

RTOG 9202(2003, 2008)

1554 T2c-4, N0 28 vs 4 OS for Gl 8-10

EORTC 22961(2009)

970 T2c-4, N+ 36 vs 6 OS

Canada PCS IV(ASCO 2013)

630 T3 or PSA>20 or Gl 8, N0

36 vs. 18 No difference

RRP and Adjuvant ADT in Node Positive Disease

Pre-PSA Era (prospective)N=98

Messing, Lancet Oncol, 2006

PSA era (retrospective)N=731

Wong, J Clin Oncol, 2009

RRP and Adjuvant RT in High Risk Disease

EORTC 22911Bolla (Lancet 2012)

SWOG 8794Thompson (J Urol 2009)

ARO 9602Wiegel (JCO 2009, GU ASCO 2013)

Eligibility pT2-3N0 ece, svi, or margin+

pT2-3N0 ece, svi, or margin+

pT3N0 ece, svi, or margin+

N n=1005 30% PSA >0.2 ng/ml 

n=425 33% PSA >0.2 ng/ml 

n=307 20% PSA >0.1 ng/ml

Follow up, years

10.6  11.5 9.3

Outcome (primary)

Biochemicaland local control

MFS(also OS)

Biochemical(Too few events for MFS and OS; main benefit for margin+) 

•Adjuvant and early salvage not directly compared; may enjoy similar benefits?•Node positive disease not evaluated

RTOG 9601N= 760Salvage RT

Shipley WU N Engl J Med, 2017

• Benefit for Overall Survival at 12 years:76.3% bicalutamide vs 71.3% placebo

•Post hoc risk analysis suggests less benefit:Gleason <= 7PSA < 0.7negative margins

Treatment of Hormone-Sensitive Disease

NCIC/PR7: Intermittent vs. ContinuousNon-Metastatic Disease after RT

Crook JM N Engl J Med, 2012

IAD is noninferior to CAD with respect to OS

SWOG 9346: Intermittent vs. Continuous Metastatic Disease

Hussain N Engl J Med 2013

Intermittent is NOT not inferior to Continous therapy in metastatic HSPCTRANSLATION: Intermittent is POTENTIALLY inferior

(lower boundary of CI <1.00 is inconclusive)

HR 1.10; 90% CI, 0.99-1.23CI exceeded upper boundary for noninferiority = 1.20

SUMMARYHormone Sensitive Prostate Cancer Intermittent versus Continuous• NCIC/PR7 - non-metastatic – NS

difference• SWOG 9346 – metastatic – HR 1.10

(intermittent potentially inferior)• Intermittent reasonable option for patients

with non-metastatic prostate cancer• For patients with metastases, needs to be

individualized

HORMONE-SENSITIVEDiagnosis161, 360

CASTRATION -RESISTANTDeaths From Disease

26, 730

Prostate Cancer Clinical States

ClinicallyLocalizedDisease

Docetaxel2004

Sipuleucel -T2010

Cabazitaxel2010

Abiraterone2011

Enzalutamide2012

Abiraterone2012

Alpharadin2013

Enzalutamide2014

Docetaxel2015

Active Surveillance

Surgery

Radiation +/- ADT

Olaparib2016

BiochemicalRecurrence

(PSA)Metastatic Non-

Metastatic

MetastaticFirst-Line

Treatment

MetastaticPost-Chemo

Intermittent

ADT

Continuous ADT

3 trials of Docetaxel in metastatic hormone-sensitive prostate cancer; 2 with OS benefit, suggestion of most benefit in 

“high volume” disease

Metastatic Hormone Sensitive PC: GETUG 15 Trial Design

GETUG- 15:Overall Survival= Negative Trial

LANDMARK STUDYMetastatic Hormone Sensitive PC: ECOG 3805 (CHAARTED)

Sweeney C N Engl J Med, 2015

Metastatic Hormone Sensitive PC: ECOG 3805 (CHAARTED)Overall Survival

Sweeney C N Engl J Med, 2015

Metastatic Hormone Sensitive PC: ECOG 3805 (CHAARTED)High vs Low Volume Disease

Sweeney C N Engl J Med, 2015

Clinical benefit of Docetaxel x 6 cycles most pronounced in patients with high voume disease

Hormone Sensitive Prostate Cancer (M0 and M1)STAMPEDE

James ND, Lancet, 2015

Hormone Sensitive Prostate Cancer (M0 and M1)STAMPEDE

Treatment ofCastration Resistant

Metastatic Prostate Cancer

OS Benefit in Recent mCRPC Trials

LANDMARK STUDY

Proof of Principle that the Androgen Receptor is relevant even in advanced castration resistant disease

Modified from Ang, et al, British Journal of Cancer, 2009

Secondary Mineralicorticoid Syndrome

Suppression of the Renin-Angiotensin Pathway

Abiraterone AcetateSelective and Irreversible Inhibition of CYP17

Agent Trial Median Overall  Survival

Hazard Ratio

Abiraterone/prednisonevs placebo/prednisone

COU-301-AA: POST DOCETAXELDeBono et al, NEJM 2011

3.7 months14.8 vs.10.9

0.65

Abiraterone/prednisonevs placebo/prednisone

COU-302-AA: PRE-DOCETAXELRyan et al, NEJM 2013

5.2 months35.3 vs. 30.1

0.79

Ryan CJ N Engl J Med 2013

Abiraterone AcetateAdverse Events of Special Interest

EnzalutamideA Second Generation AR Antagonist

Chen et al., Lancet Oncology, 2009

Enzalutamide  vs Placebo Trial Median Overall  Survival  Hazard Ratio

AFFIRM: POST DOCETAXEL (Scher et al, NEJM 2012) 4.8 months (18.4 vs. 13.6) 0.63

PREVAIL: PRE-DOCETAXEL    (Beer et al, NEJM 2014) 2.2 months (32.4 vs. 30.2) 0.71

Enzalutamide

Enzalutamide:

1. Binds with higher affinity

2. Impairs nuclear translocation

3. Prevents DNA binding 

EnzalutamideMost common AE and Events of Interest

•  The most common grade >= 3 AE was HTN (7% enzalutamide)

•The most common cardiac event was Afib (2% enzalutamide)

• One patient in each study group had a seizure

Beer TM N Engl J Med, 2014

• AR antagonist drug class causes convulsions in laboratory animals at high doses by an off-target mechanism of GABA-A inhibition1

• AR antagonist seizure risk increases with brain drug concentrations1

• Seizures have been observed in clinical testing of next generation AR antagonists such as BMS-641988 and enzalutamide 2,3

1Foster WR et al., Prostate, 20112Rathkopf D et al., Clin Cancer Res, 2011; 3Scher HI et al., Lancet, 2010.

Seizure potential andthe development of AR antagonists

AR Ligand Binding Domain Mutations Associated With AR Resistance

W742C (741): Bicalutamide

AR point mutations*

H875Y (874): Flutamide

F877L (876): Enzalutamide/ARN-509

T878A (877): Abiraterone

C-terminal ligand binding domain

Hinge region

Normal AR protein

AR v7 splice variant(Antonarakis et al., 2014)

N-terminal effector domain DNA binding domain

AR v567 splice variant(Thadani-Mulero et al, 2014.)

Figure modified from Bambury R , Seminars in Urol Oncol. 2015*Current (former) nomenclature per AR Gene Mutations Database

• No patients had the AR F876L mutation at baseline (N=30)

• 3 of 29 evaluable patients developed the AR F876L mutation at progression using the Beaming digital PCR assay

Phase I Study of Apalutamide: Patient Example of Acquired AR F876L

Mutation

m, mutation; WT, wild type.

Joseph JD, et al. Cancer Discov. 2013;3:1020-1029. 

Best PSA Responses According to AR-V7 Status

Antonarakis ES N Engl J Med 2014

Enzalutamide Abiraterone

No patients with ARV7 had a significant response to AR therapy

Multi-Insitutional Genomic Profiling of Patients with mCRPC

Robinson Cell 2015

49%71.3%

12.7%

90% metastatic CRPC with actionable mutations

The results of the TOPARP-A trial suggest that a common subset of metastatic prostate cancers can be molecularly stratified for treatment

Mateo J, et al. NEJM, 2015

January 28th- 2016-FDA Grants Olaparib Breakthrough Designation in mCRPC

Olaparib received an FDA breakthrough therapy designation as a treatment for patients with BRCA1/2 or ATM-mutated mCRPC in those who have received a prior taxane-based chemotherapy and at least either hormonal agent enzalutamide or abiraterone acetate.

Evolution of Chemotherapy in mCRPC

• 1985: No evidence for palliative benefit from chemotherapy. Chemotherapy recommended only for clinical trials.

• 1996: Mitoxantrone + prednisone vs prednisone alone establishes a palliative benefit for mitoxantrone in 30% of symptomatic patients. Studies are too small to detect a survival benefit. FDA approval.

• 2004: The larger TAX327 and SWOG 99-16 trials show a 3 month improvement in survival (1619 months) for Docetaxel compared to Mitoxantrone. FDA

approval.

TAX 327 Established Docetaxel as the First-Line Standard of Care for Castration-Resistant Prostate Cancer:

Benefit Was Restricted to Every 3 Week Dosing

Months

Mediansurvival Hazard

(mos) ratio P-value Docetaxel every 3 weeks: 18.9 0.76 0.009Docetaxel weekly: 17.3 0.91 0.3Mitoxantrone 16.4 – –

Prob

abili

ty o

f Sur

vivi

ng

0 6 12 18 24 300.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3 wklyDocetaxel wklyMitoxantrone

Tannock et al., NEJM, 351:1502, 2004

TROPIC: Phase III StudyCabazitaxel after Docetaxel in MCPRC

De Bono J Lancet 2010

Cabazitaxel in mCRPC (TROPIC)Primary Endpoint: Overall Survival

Granulocytopenia fever 7%: Consider prophylactic growth factor support in those at higher risk (multiple risk factors)

PROSELICA: non-inferiority studyCabazitaxel 25 mg/m2 (C25) vs 20 mg/m2 (C20)

C20 is non-inferior for OS compared with C25 and C20 demonstrated an improved safety profile

Modified from de Bono JS ASCO Annual Meeting 2016

C20 N-598

C25N=602

Grade 3-4 AE 39.7% 54.5%

Grade 4 Neutropenia

21.3% 48.6%

Neutropenic infection

2.2% 6.1%

OS Benefit in Recent mCRPC Trials

Sipuleucel-T: Mechanism of Action

Randomized Phase 3 IMPACT Trial(Immunotherapy Prostate Adenocarcinoma Treatment)

IMPACT Overall SurvivalFinal Analysis (349 events)

Sipuleucel-T Questions

• While this was a breakthrough in terms of validating a new MOA and validating the principles of immunotherapy, the acceptance and adoption have been slow:

– Controversial MOA- does it really work the way we thought?

– Few PSA declines– No measurable prolongation in TTP– Other agents with more “straightforward”

MOAs have been developed– Cost

Slide courtesy of PW Kantoff

ResponderN=28

Cycle 1 PSA (ng/ml) every 3-weeks and nadir Measurable Disease at Baseline

Best Radiologic Response

1 April 2015 70.65 → 11.11 → 1.18 → 0.11 → 0.08 Yes (lymph) PR

2 October 2015 46.09 → 41.22 → 12.99 → 9.89 → 0.02 No n/a

3 January 2016 2502.75 → 1.26 → 0.07 →0.01 → <0.01 Yes (liver) PR

4 March 2016 82.43 → 17.34 → 0.3 → 0.01 No n/a

5 June 2016 250 → 88.69 → 5.1 → 0.43 → 0.18 Yes (liver) PR

Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer

Modified from Graff et al., ESMO 2016

None of the responders have relapsed as of 10/2016.

Modified from Graff et al., Oncotarget 2016

OS Benefit in Recent mCRPC Trials

Radium- 223 Targets Bone Metastases

ALSYMPCA Phase III Study Design

Parker C N Engl J Med 2013

ALSYMPCA TRIALRadium - 223 in mCRPC

Significantly improved OS by 3.6 mos

Significantly improved time to first SSE by 5 mos

Parker C N Engl J Med 2013

ALSYMPCA Adverse Events of Interest

Parker C N Engl J Med 2013

Prevention of skeletal-related events (SREs) in men with metastatic CRPC

Phase III Double- Blind Study of Denosumab vs Zolendronic Acid in mCRPC

Fizazi K Lancet 2011

ConclusionsPrevention of SREs

• Denosumab was superior to Zoledronic Acid in delaying SRE (18% risk reduction).

• The incidence of ONJ was higher in the Denosumab group but this was not statistically significant (2.3% vs. 1.3%; p=0.09).

• There was no benefit in terms of PSA, Disease progression, or overall survival.

Bone protective agents zoledronic acid or denosumab are reasonable alternatives

(NCCN guidelines)

FINAL THOUGHTSScreening and Prevention

• ACS, NCCN, AUA, USPSTF do NOT recommend universal PSA screening

• SELECT TRIAL: Vitamin E may increase risk

• PCPT (and REDUCE) trials: alpha reductase inhibitors have no effect on OS

FINAL THOUGHTSTreatment Localized Disease

• Primary ADT is NOT recommended

• 3 TRIALS comparing primary treatment:- SPCG-4: most benefit from RP if <65, intermediate risk PC- PIVOT: RP did not reduce all cause or PCSM- ProtecT: RP and RT reduce disease progression but PCSM is low

regardless of assigned treatment arm

• Adjuvant and Salvage RT are both reasonable

FINAL THOUGHTSTreatment HSPC• Intermittent ADT for non-metastatic disease after

RT is reasonable (NCIC/PR7)

• Intermittent ADT for metastatic disease is potentially inferior to continuous ADT (SWOG 9346); personalize approach to patient

• Docetaxel is a standard of care for newly diagnosed metastatic HSPC assuming acceptable comorbidities; most benefit is in “high volume” disease (ECOG3805, STAMPEDE)

FINAL THOUGHTSTreatment mCRPC• Abiraterone and Enzalutamide are approved both

pre and post Docetaxel (COU-301, COU-302, PREVAIL, AFFIRM); it is as of yet unknown how best to sequence these agents

• AR is overexpressed in mCRPC; AR point mutations and ARV7 splice variants may act as predictive biomarkers for response to treatment

• Olaparib has activity in mCRPC patients with DNA mismatch repair deficiencies (TOPARP-A)