ConnuingCareforYourPaentswith(...

Con$nuing Care for Your Pa$ents with Metasta$c CRPC

Michael S. Cookson, MD, MMHC Professor and Chair

Department of Urology University of Oklahoma Health Science Center

27th Annual InternaAonal Prostate Cancer Symposium Update January 26, 2017

Overview

•  IntroducAon •  Urologists as the Primary Caregiver •  Establishing a MulAdisciplinary CRPC Clinic •  Evidenced Based TherapeuAc OpAons •  Conclusions

Lesson #1

The Urologist should be the primary caregiver for men with Prostate Cancer

This includes paAents as they progress through the “disease spectrum” and

especially those with CRPC

Urologist as the Primary Caregiver

•  PaAents progress through disease spectrum, but should not have to progress through specialists!

•  Role of the Urologist –  Diagnose and treat prostate cancer –  Understand the progression of the disease –  Understand the management of the progression –  Coordinate the care between specialists

Lesson #2

“Establish, organize and manage a MulAdisciplinary CRPC Clinic

that incorporates your available resources and works best for your clinical healthcare environment ”

MulAdisciplinary CRPC Clinic •   In response to the changing landscape, clinicians are altering care delivery to incorporate these treatments

•   Even with guidelines, the breadth of treatment opAons allows for alternaAve views on Aming and sequencing of agents

•   One approach includes Shared Pa$ent Care in a MDC •   Reports from MDCs show high paAent saAsfacAon rates, improved classificaAon of disease and clinical outcomes

•   Studies of other tumors have also provided evidence that a MDC approach may impact paAent survival

Models for Establishing a MulAdisciplinary CRPC Clinic

ALL-‐IN-‐ONE MDC

MulAdisciplinary CRPC Clinic •  CriAcal step is determining clinic structure •   Established clinics show an all-‐in-‐one approach may be most efficient, parAcularly from paAent point of view

•  Discuss treatment with specialists on the same day •  Decreases Ame and travel burden on paAents while improving communicaAon; potenAally increasing acceptance into clinical trials

MulAdisciplinary CRPC Clinic

•  However, Ame and space limitaAons may prevent widespread use of the all-‐in-‐one model

•   Furthermore the all-‐in-‐one clinic may reduce producAvity and have financial disincenAves

•  Obstacles to implemenAng a MDC at a single locaAon can be managed by a virtual MDC

MulAdisciplinary CRPC Clinic

•   Two alternaAve approaches to the all-‐in-‐one MDC are the same day/different clinic and the different day/different clinic models

•   For providers with clinic locaAons in proximity, paAents can be evaluated on the same day between the clinics

•  Care may then be coordinated through group meeAng, tumor boards or messaging among providers

Models for Establishing a MulA-‐Disciplinary CRPC Clinic

Virtual MDC Models 1. Same day/different clinic 2. Different day/different clinic

MDC CRPC: Key Ingredients

•  PaAent Navigator •  Physician Assistants and/or Nurse PracAAoners •  Weekly meeAngs w/ MulAD specialist: Tumor Boards •   Shared EMR (if possible) •  PCP to manage comorbid condiAons •   SupporAve care, nutriAonists, and pain management

Lesson #3

“Offer Evidence Based TherapeuAc OpAons for paAents with metastaAc CRPC – GUIDELINES (AUA, NCCN, EAU)”

Local Therapy

Androgen Deprivation

Therapies After LHRH Agonists

and Antiandrogens

Chemotherapy

Postchemotherapy

Death

mCRPC Changing Landscape

Surgery / Radiation

Traditional Androgen Deprivation Therapy

Antiandrogen

Sipuleucel-T Cabazitaxel

Abiraterone or Enzalutamide

Docetaxel

Radiation Therapy

AAW

Asymptomatic/Minimally symptomatic Symptomatic

Radium-223

Prostate Cancer. NCCN Guidelines. v3.2016, AUA CRPC Guidelines, 2016.

CLINICAL GUIDANCE

Since the approval of docetaxel in 2004, the first drug to offer survival benefits for CRPC paAents, five addiAonal agents have demonstrated a survival benefit and have now been approved on the basis of randomized clinical trials.

•  Abiraterone •  Cabazitaxel •  Enzalutamide •  Radium 223 •  Sipuleucel-‐T

TREATMENT EVOLUTION

2004: Docetaxel

Tannock 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: Abiraterone Ryan et al.

(COU-‐AA-‐302)

2005 2007 2009 2011 2013

2013: Radium 223 Parker et al. (ALSYMPCA)

2014

2014: Enzalutamide Beer et al. (PREVAIL)

While the greater availability of treatment agents benefits paAents, the mulAple opAons and sequencing of medicaAons complicates clinical decision-‐making.

INDEX PATIENTS

To assist in clinical decision-‐making, six index pa$ents were developed represen$ng the most common clinical scenarios that are encountered in clinical prac$ce

These index pa$ents were created based on the following: 1. Presence or absence of metasta$c disease 2. Degree and severity of symptoms 3. Pa$ents’performance status (ECOG scale) 4. Prior docetaxel chemotherapy

INDEX PATIENTS

1.   Asymptoma$c non-‐metasta$c CRPC 2.   Asymptoma$c or minimally-‐symptoma$c, mCRPC without prior docetaxel 3.   Symptoma$c, mCRPC with good performance status and no prior docetaxel 4.   Symptoma$c, mCRPC with poor performance status and no prior docetaxel 5.   Symptoma$c, mCRPC with good performance status and prior docetaxel 6.   Symptoma$c, mCRPC with poor performance status and prior docetaxel

INDEX PATIENT 1

Asymptoma$c non-‐metasta$c CRPC (M0)

Clinicians should recommend observa2on with con2nued androgen depriva2on to pa2ents with non-‐metasta2c CRPC. (Recommenda*on; Evidence Level Grade C)

Clinicians may offer treatment with first-‐ genera2on an2-‐androgens (flutamide, bicalutamide and nilutamide) or first-‐genera2on androgen synthesis inhibitors (ketoconazole+steroid) to select pa2ents who are unwilling to accept observa2on. (Op*on; Evidence Level Grade C)

Clinicians should NOT offer systemic chemotherapy or immunotherapy to pa*ents with outside the context of a clinical trial. (Recommenda*on; Evidence Level Grade C)

INDEX PATIENT 2

Asymptoma$c or minimally symptoma$c, metasta$c mCRPC (M1) without prior docetaxel chemotherapy

Clinicians should offer abiraterone + prednisone, enzalutamide, docetaxel or sipuleucel-‐T to pa*ents with good performance status. [Standard; Evidence Level Grade A (abiraterone+prednisone and enzalutamide) / B (docetaxel and sipuleucel-‐T)]

Clinicians may offer first-‐ genera*on an*-‐androgen therapy, ketoconazole + steroid or observa*on who do not want or cannot have one of the standard therapies. (Op*on; Evidence Level Grade C)

ABIRATERONE: COU-‐302

COU-‐AA-‐302: 1,088 men with mCRPC who had not received prior chemotherapy

Prednisone 5mg twice daily plus 1,000mg abiraterone daily OR placebo

ParAcipants receiving abiraterone had staAsAcally significantly bemer radiographic progression-‐free and overall survival (HR = 0.53, p<0.001 and HR= 0.75, p= 0.01, respecAvely)

Ryan et al. NEJM 2013

ABIRATERONE: COU-‐302

Ryan et al. Lancet Oncology 2015

ENZALUTAMIDE: PREVAIL The Phase III PREVAIL trial evalua$ng enzalutamide versus placebo in 1,717 chemotherapy-‐naive men with asymptoma$c or mildly symptoma$c mCRPC (including some with visceral metastases) was stopped a`er a planned interim analysis conducted when 540 deaths had been reported

•   Enzalutamide (160mg/day) •   Placebo

Overall survival HR 0.706, 95% CI [0.60-‐0.84] P<0.001 Radiographic progression-‐free survival HR 0.186, 95% CI [0.15-‐0.23]

Beer T, et al. NEJM 2014

ENZALUTAMIDE: PREVAIL

Beer T, et al. NEJM 2014

Co-primary

Endpoints:

•  rPFS •  Overall survival

Enzalutamide

160 mg/day n = 872

(ADT was maintained)

Pa$ent Popula$on: •  1717 men with progressive mCRPC

•  Asymptoma$c/ mildly symptoma$c

•  Chemotherapy-‐naïve

•  Steroids allowed but not required

•  Prior an$androgens allowed but not required

•  Pa$ents with visceral disease (liver and/or lung) allowed

R A N D O M I Z E D 1:1

Placebo n = 845

(ADT was maintained)

ADT=androgen deprivaAon therapy.

PREVAIL: Co-‐Primary Endpoints

PFS

OS

81% decreased risk of

progression or death

29% decreased risk of death

*Median OS follow-up: ~22 months Armstrong AJ. ASCO 2014, abstract 5007.

ENZALUTAMIDE: OVERALL SURVIVAL ENZALUTAMIDE: PREVAIL

DOCETAXEL: TAX-‐327

TAX-‐327 included 1,006 men with mCRPC and good performance status

5 mg prednisone twice daily plus docetaxel 75mg every three weeks

OR docetaxel 30mg weekly for five of every six weeks OR mitoxantrone 12mg every three weeks

PaAents who received docetaxel every three weeks showed significantly bemer survival than those receiving mitoxantrone (HR= 0.76, p= 0.009).

Tannock et al. NEJM 2004

TAX-‐327 OVERALL SURVIVAL

Median OS

Hazard ratio

P value

Doc q3w 19.2 0.79 0.004 Doc weekly 17.8 0.87 0.086 Mitoxantrone 16.3 – –

0

Time (years)

0.2

0.6

3

0.4

0.8

1.0

5 6 7

Docetaxel q3w Docetaxel q1w

Prop

or$o

n alive

0

Mitoxantrone

1 4 2

Berthold DR et al. J Clin Oncol 2008;26:242–245

SIPULEUCEL-‐T: IMPACT

The IMPACT trial included 512 men with asymptoma$c or minimally symptoma$c mCRPC and good func$onal status

PaAents received either sipuleucel-‐T or placebo on a 2:1 basis.

Compared to placebo, sipuleucel-‐T was associated with a relaAve reducAon of 22% in the risk of death (HR= 0.78, p= 0.03).

Some have criAcized the IMPACT trial, noAng that it failed to show an advantage for acAve agent in the trial’s second endpoint (progression-‐free survival).

Kantoff et al. NEJM 2010

SIPULEUCEL-‐T: IMPACT

Kantoff et al. NEJM 2010

HR = 0.775 (95% CI: 0.614, 0.979) Survival Benefit = 4.1 months P = 0.032 (Cox Model)

Median Survival: Sipuleucel-‐T (n=341) 25.8 Mos. Placebo (n=171) 21.7 Mos.

INDEX PATIENT 3

Symptoma$c, mCRPC with good performance status and no prior docetaxel chemotherapy

Clinicians should offer abiraterone + prednisone, enzalutamide or docetaxel to pa*ents with symptoma*c, mCRPC with good performance status and no prior docetaxel chemotherapy. [Standard; Evidence Level Grade A (abiraterone + prednisone and enzalutamid/ B (docetaxel)]

Clinicians may offer ketoconazole + steroid, mitoxantrone or radionuclide therapy to pa*ents who do not want or cannot have one of the standard therapies. [Op*on; Evidence Level Grade C (ketoconazole) /B (mitoxantrone) / C (radionuclide therapy)]

INDEX PATIENT 3

Symptoma$c, mCRPC with good performance status and no prior docetaxel chemotherapy

Clinicians should offer radium-‐223 to pa2ents with symptoms from bony metastases from mCRPC with good performance status and no prior docetaxel chemotherapy and without known visceral disease. (Standard; Evidence Level Grade B) Clinicians should NOT offer treatment with either estramus*ne or sipuleucel-‐T to pa*ents with symptoma*c, mCRPC (Recommenda*on; Evidence Level Grade C)

RADIUM-‐223 PaAents 1,2 StraAficaAon2 Treatment1,2

N=921

•  CRPC with symptomaAc bone metastases •  No known visceral metastases

•   Prior docetaxel: Yes vs No •   Current bisphosphonate use: Yes vs No

•   Total alkaline phosphatase (ALP): <220 U/L vs >220 U/L

Radium Ra223 dichloride (50 kBq/kg) + best standard of care (n=614)

6 injec$ons at 4-‐week intervals

Placebo (saline) + best standard of care (n=307) 136 centers in 19 countries

•   Included paAents with malignant lymphadenopathy up to 3cm1

•   Best standard of care included: local external beam radiaAon therapy (EBRT), corAcosteroids, anAandrogens, estrogens, estramusAne, or ketoconazole1 1. Radium RA 223 dichloride injecAon; 2. Parker C, et al. N Engl J Med. 2013;369:213-‐223.

RADIUM-‐223

radium Ra 223 dichloride*

Placebo*

radium Ra 223 614 578 504 369 277 178 105 60 41 18 7 1 0 0 dichloride

placebo 307 288 228 157 105 67 39 24 14 7 4 2 1 0

30% reducAon in the risk of death vs placebo (HR=0.695) *Plus best standard of care; *95% Cl: 0.581-‐0.832 for the exploratory updated analysis.

Placebo median OS: 11.3 months (95% Cl: 10.4-‐12.8)

Radium Ra 223 dichloride median OS: 14.9 months (95% Cl:

13.9-‐16.1)

INDEX PATIENT 5

Symptoma$c, mCRPC with good performance status and prior docetaxel chemotherapy

Clinicians should offer treatment with abiraterone + prednisone, cabazitaxel or enzalutamide. If the pa*ent received abiraterone + prednisone or enzalutamide prior to docetaxel chemotherapy, he should be offered cabazitaxel. [Standard; Evidence Level Grade A (abiraterone) /B (cabazitaxel) /A (enzalutamide)]

CABAZITAXEL

An open-‐label, randomized Phase III trial included 755 pa$ents who had received prior docetaxel

•  25mg cabazitaxel intravenously with oral prednisone every three weeks •  12mg mitoxantrone intravenously with oral prednisone every three weeks

Cabazitaxel demonstrated improved overall survival (15.1 months v. 12.7 months) and improved progression-‐free survival (2.8 months v. 1.4 months).

de Bono et al. Lancet 2010

CABAZITAXEL

de Bono et al. Lancet 2010

HR = 0.70 (95% CI: 0.59, 0.83) P < 0.0001 30% reduc$on in rela$ve risk of death

Cabazitaxel Median Survival: 15.1 Mos.

Mitoxantrone Median Survival: 12.7 Mos.

OS Benefit in Recent CRPC TrialsTrial/

Agent/Date

Approved

Mechanism Comparator Survival(months)

Hazard Ratio P-value Reference

AFFIRMEnzalutamide

Androgen Receptor Signaling Inhibitor

Placebo 18.4 vs. 13.6 0.631 <0.0001

de Bono et al, ASCO

2012

COU-AA-301 Abiraterone

+ prednisone 2011

CYP17 Inhibitor Placebo +prednisone 14.8 vs. 10.9 0.646 <0.0001

de Bono et al, NEJM

2011

TROPIC Cabazitaxel

+ prednisone2010

Cytotoxic Mitoxantrone +prednisone 15.1 vs. 12.7 0.70 <0.0001

de Bono et al, Lancet

2010

Radium 223*Alpha-particle

emitting radionuclide

Placebo 14.9 vs 11.3 0.69 0.0018 Parker et al, ESMO 2011

*Radium-223 trial included chemotherapy-ineligible men †Visceral disease allowed

†

†

Post Chemotherapy Clinical Trials

Future DirecAons: M0 CRPC

Many clinical trials currently underway

•   P3, multinational, randomized, placebo-controlled study

•   Primary endpoint: Metastasis-free survival*

N = 1560

Patients with nonmetastatic CRPC

No prior chemotherapy

Recrui$ng Planned Evaluations §   Metastasis-free survival §   Overall survival §   Time to pain progression §   Time to opiate use for prostate cancer pain §   Time to first use of cytotoxic chemotherapy §   Time to first use of new antineoplastic therapy §   PSA response rates §   Time to PSA progression §   Time to functional status deterioration as

assessed by the FACT-P global score §   Quality of life as assessed by the EQ-5D-5L

health questionnaire and QLQ-PR25 module §   Safety

* Defined as the *me from randomiza*on to radiographic progression or death on study CRPC = castra*on-‐resistant prostate cancer; EQ-‐5D-‐5L = European quality of life-‐5 dimensions-‐5 levels; FACT-‐P = func*onal assessment of cancer therapy-‐prostate; PSA = prostate-‐specific an*gen; QLQ-‐PR25 = quality of life ques*onnaire-‐prostate 25; R = randomized

R 2:1

Enzalutamide 160 mg qd +

ADT n = 1040

Placebo+ ADT

n = 520

www.clinicaltrials.gov (NCT02003924)

M0 CRPC -‐ PROSPER: Enzalutumide

N=1200 M0 CRPC; ECOG 0 or 1 No prior treatment with second generaAon hormonal agents, radiopharmaceuAcal agents, chemotherapy, or other invesAgaAonal agents, or history of or predisposiAon to seizure

R 2:1

ARN-‐509 240 mg/d + ADT

Placebo + ADT

Primary Endpoint •  Metastasis Free Survival (MFS)

Key Secondary Endpoints •  Overall Survival (OS) •  Time to symptomaAc radiographic progression •  Time to iniAaAon of cytotoxic chemotherapy •  Radiographic Progression Free Survival (rPFS) •  Time to metastasis •  QOL: change in FACT-‐P and EQ-‐5D quesAonnaire scores •  Adverse events (MedDRA) •  PharmacokineAcs

Recruiting


M0 CRPC - SPARTAN: ARN-‐509

N=1500 M0 CRPC, prostate-‐specific anAgen doubling Ame of ≤ 10 months and PSA > 2 ng/ml, ECOG 0-‐1 No prior treatment with: second generaAon androgen receptor inhibitors, other invesAgaAonal AR inhibitors, or CYP17 enzyme inhibitor or prior chemotherapy or immunotherapy

R 2:1

ODM-201 300 mg bid +

ADT

Placebo + ADT

Primary Endpoint •  Metastasis-‐Free Survival

Key Secondary Endpoints •  OS •  Time to first symptomaAc skeletal event •  Time to iniAaAon of chemotherapy •  Time to pain progression

Recruiting


M0 CRPC - ARAMIS: ODM-201

SPECTRUM OF DISEASE

Conclusions

•  Urologists should be the Primary Caregiver for men with Advanced Prostate Cancer

•  Establishing a MulAdisciplinary CRPC Clinic is an essenAal component to care delivery

•  Evidenced Based TherapeuAc OpAons exist, and familiarity and use will enhance outcome

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