Defining Personalized Care Plans in

Metastatic Castration-Resistant

Prostate Cancer

Tanya B. Dorff, MD

Associate Professor of Clinical Medicine

USC Keck School of Medicine

USC Norris Comprehensive Cancer Center

ACCREDITATIONThis activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and i3 Health. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

The Postgraduate Institute for Medicine designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

The Postgraduate Institute for Medicine is accredited with distinction as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. This educational activity for 1.0 contact hours is provided by Postgraduate Institute for Medicine. Designated for 0.8 contact hours of pharmacotherapy credit for Advance Practice Registered Nurses.

INSTRUCTIONS TO RECEIVE CREDITIn order to receive credit for this activity, participants must:1. Participate in the live webinar2. Complete and submit the posttest and activity evaluation via the link provided after the webinar3. Download or print their Certificate of Credit

UNAPPROVED USE DISCLOSUREThis educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

COMMERCIAL SUPPORTThis activity is supported by independent educational grants from Bayer HealthCare Pharmaceuticals Inc. and Genzyme.

Disclosures

▶ Dr. Dorff discloses the following commercial

relationships:◼ Consultant: Bayer, Dendreon, Eisai, EMD Serono, Exelixis,

Janssen

◼ Speakers’ Bureau: Exelixis

▶ The PIM planners and managers, Trace Hutchison,

PharmD, Samantha Mattiucci, PharmD, CHCP, Judi

Smelker-Mitchek, MBA, MSN, RN, and Jan Schultz,

MSN, RN, CHCP have nothing to disclose

▶ The i3 Health planners and managers have nothing to

disclose

Learning Objectives

▶ Evaluate recent study findings on combination and

sequential treatment strategies for patients with

metastatic CRPC

▶ Determine which predictive/prognostic biomarker

tests are ready for application in metastatic CRPC

practice

▶ Utilize strategies for evaluating treatment response,

incorporating imaging studies, prostate-specific

antigen levels, and clinical findings

CRPC = castration-resistant prostate cancer.

Mr. JW: 57-Year-Old Man

PSA = prostate-specific antigen; LE = lower extremity.

◼ PSA 125 ng/mL

◼ Gleason 5+5

◼ Osseous metastases

◼ L3-L4 epidural

extension of tumor with

LE weakness

◼ Received degarelix

April 2013 + surgical

decompression and

radiation

◼ PSA dropped to

0.06 ng/mL within 3 mo

◼ Developed early

castration resistance at 6

months with PSA rising to

0.48 ng/mL and then 1.1

ng/mL

◼ Asymptomatic

Diagnosis

Castration

ResistanceInitial Therapy

Mr. JW: Castration Resistance

Mr. JW: Next Step?

Sipuleucel-T

Abiraterone

Enzalutamide

DocetaxelCabazitaxel

Radium-223

Combination Therapy

Treatment Options

New “Life Extending Therapies” for

Metastatic CRPC

▶ Abiraterone◼ COU301: Median OS 14.8 vs 10.9 mo for placebo (post-TAX)

◼ COU302: PFS 16.5 vs 8.3 mo for placebo (pre-TAX)

▶ Cabazitaxel◼ Median OS 15.1 vs 12.7 mo mitoxantrone (post-TAX)

▶ Enzalutamide◼ AFFIRM: Median OS 18.4 mo vs 13.6 mo for placebo (post-

TAX)

◼ PREVAIL: Median OS 32.4 mo vs 30.2 mo pre-TAX (17 mo

delay in chemo)

OS = overall survival; TAX = taxane therapy; PFS = progression-free survival.

de Bono et al, 2011; Rathkopf et al, 2014; de Bono et al, 2010; Scher et al, 2012; Beer et al, 2014.

New “Life Extending Therapies” for

Metastatic CRPC (cont.)

▶ Radium-223◼ ALSYMPCA: Median OS 14.9 vs 11.3 mo for placebo

▶ Sipuleucel-T◼ IMPACT: Median OS 23.2 vs 18.9 mo for placebo

Parker et al, 2013; Higano et al, 2009.

Metastatic CRPC: Defining a

“Meaningful” Improvement in OS

Schellhammer et al, 2013.

▶ Autologous activated cellular immunotherapy

Sipuleucel-T Immunotherapy

Kantoff et al, 2010.

Sipuleucel-T

Sipuleucel-T Immunotherapy (cont.)

Higano et al, 2009.

Abiraterone (CYP17 Inhibitor)

Boron & Boulpaep, 2003.

OS HR=0.79 for AA+P

Pre-Docetaxel (P=0.019)

COU302 Trial: Abiraterone

AA + P = abiraterone acetate + prednisone.

Rathkopf et al, 2014.

Abiraterone: Adverse Events

de Bono et al, 2011.

Enzalutamide:

Androgen Receptor Antagonist

Image courtesy of Tanya B. Dorff, MD.

PREVAIL Trial:

Enzalutamide vs Placebo

Beer et al, 2014.

Enzalutamide: Adverse Events

Beer et al, 2014.

Petrylak et al, 2004.

SWOG 9916:

Docetaxel in Metastatic CRPC

TAX 327:

Docetaxel in Metastatic CRPC

Tannock et al, 2004.

Docetaxel: Adverse Events

Tannock et al, 2004.

TREATMENT

6 injections at 4-week intervals

Radium-223

(50 kBq/kg)

+ Best BSC

Placebo (saline)

+ BSC

R

A

N

D

O

M

I

Z

E

D

2:1

N=921

PATIENTS

Confirmed

symptomatic

CRPC

≥2 bone

metastases

No known

visceral

metastases

Post-

docetaxel or

unfit for

docetaxel

Total ALP:

<220 U/L vs ≥220 U/L

Bisphosphonate use:

Yes vs No

Prior docetaxel:

Yes vs No

STRATIFICATION

ALSYMPCA Phase III:

Radium-223 vs BSC

BSC = best standard of care; ALP = alkaline phosphatase; U/L = units per liter.

Parker et al, 2013.

ALSYMPCA: Overall Survival

Parker et al, 2013.

ALSYMPCA: Time to First

Symptomatic Skeletal Event

Parker et al, 2016.

ALSYMPCA: Adverse Events

Parker et al, 2013.

Mr. JW (cont.)

How would you treat this patient?

a. Abiraterone

b. Docetaxel

c. Enzalutamide

d. Sipuleucel-T

e. Other (including combinations)

Considerations for This Patient

▶ Abiraterone◼ Impaired insulin sensitivity

▶ Enzalutamide◼ History of seizures or falls

◼ Visceral disease

▶ Docetaxel◼ Neuropathy (could substitute cabazitaxel)

◼ Risk of infection

▶ Radium-223◼ Symptomatic bone metastases without soft tissue

▶ Sipuleucel-T◼ Venous access (pheresis catheter increases risk of morbidity)

Oudard et al, 2017; NCCN, 2017.

Add bone support

with zoledronic

acid or denosumab!

Novel Combination Strategies

Trial Agents Accrual (N) Status

CTSU A031201Enza

Enza + AbiN=1,311 Completed 8/31/16

Bayer 16544

Rad223

Rad223 + Abi

Rad223 + Enza

N=68Resulted; ORR

favors combination

PEACE IIIEnza

Enza + Rad223N=560 Still recruiting

ERA 223Abi

Abi + Rad223N=806 Completed

NCT02218606Abi

Abi + CabazitaxelN=55 Recruiting

▶ No level 1 data YET to support combinations

▶ Single sequential remains standard outside of clinical

trial

Clinicaltrials.gov, 2017a; Clinicaltrials.gov, 2017b; Clinicaltrials.gov, 2017c;

Clinicaltrials.gov, 2017d; Clinicaltrials.gov, 2017e.

Novel Combination Strategies (cont.)

DRD = DNA repair defects.

Clinicaltrials.gov, 2017f; Hussain et al, 2016; Clinicaltrials.gov, 2017g; Clinicaltrials.gov, 2017h;

Clinicaltrials.gov, 2017i; Reichert et al, 2017.

Trial AgentsAccrual

(N)Target Status

CO39303Abi

Abi + ipatasertibN=850 AKT Accruing

NCT01576172Abi

Abi + veliparibN=148 PARP Reported

IMbassador250Enza

Enza + atezolizumabN=730 PD-L1 Accruing

NCT02257736Abi

Abi + apalutamideN=983 AR Completed

NCT03093428

Rad223

Rad223 +

pembrolizumab

N=45 PD-L1 Accruing

NCT03012321

Abi

Olaparib

Abi + olaparib

N=60 PARPAccruing

(restricted to DRD)

Mr. JW (cont.)

◼ Enrolled on clinical trial

(abiraterone with

prednisone ± dasatinib)

◼ Randomly assigned to

abiraterone

◼ Started treatment in with

baseline PSA of 5.24

ng/mL

◼ PSA decreased to

0.14 ng/mL but then

began to rise slowly

◼ PSA 2.2 ng/mL but

feeling well and no

radiographic change

May 2014 August 2015October 2014

Mr. JW (cont.)

Would you switch therapy

or add therapy?

Monitoring Treatment Response

▶ PSA change alone should not be used as a trigger to

switch therapy if patients feel well and imaging

shows no change

▶ Imaging to evaluate response recommended every

8-9 weeks during first 24 weeks, then every 12

weeks

Scher et al, 2016.

Monitoring Treatment Response (cont.)

▶ Due to “flare” phenomenon (new bone lesions

despite improvement in disease) new lesions on a

bone scan at first assessment do not constitute

disease progression◼ Requires confirmation with additional new lesions on the

following scan

▶ When new lesions detected after 12 weeks,

confirmation of progression requires persistence of

the new lesions but not additional new lesions

Scher et al, 2016.

Mr. JW (cont.)

▶ December 2015: PSA reaches 5 ng/mL and patient

reports more pain in both hips

▶ Referred for palliative radiation

▶ Patient asks about the next treatment plan

Mr. JW: 55-Year-Old Man (cont.)

How would you treat this patient now?

a. Cabazitaxel

b. Docetaxel

c. Enzalutamide

d. Radium-223

e. Other (including combinations)

Do you continue abiraterone

“adding” an agent above or do you switch?

Decreased Efficacy of AR Targeted

Therapy in Sequence

Loriot et al, 2013.

Abiraterone response after

prior treatment with enzalutamide

Enzalutamide vs Docetaxel in Men With CRPC

Progressing After Abiraterone

Decreased Efficacy of AR Targeted

Therapy in Sequence

Suzman et al, 2014.

GR = glucocorticoid receptor; SCC = small cell carcinoma; NEPC = neuroendocrine prostate cancer.

Watson et al, 2015.

Androgen Receptor Splice Variant-7

Can ARV7 Help Select Treatment?

ARV7 = androgen receptor splice variant-7.

Antonarakis et al, 2015.

ARV7 Not Associated With

Lack of Response to Docetaxel

ARV7 Predicts Less Response to Enzalutamide

Antonarakis et al, 2014.

Can ARV7 Help Select Treatment? (cont.)

Antonarakis et al, 2014.

Can ARV7 Help Select Treatment? (cont.)

ARV7 Predicts Less Response to Abiraterone

ARV7: Not Yet Ready for Use in

Treatment Selection

TBD = to be determined; CTC = circulating tumor cell;

ddPCR = droplet digital polymerase chain reaction.

Grande et al, 2016; Scher et al, 2017; Clinicaltrials.gov, 2017j.

▶ SOGUG PREMIERE trial of

enzalutamide – PSA responses seen

in ARV7+ patients

▶ ARMOR study (in ARV7 selected

population) closed for futility◼ 953 screened, 73 enrolled

◼ PSA response 13% galeterone,

42% enzalutamide

▶ ARV7 more complicated than

originally thought◼ Amount? Timing (transient)?

◼ Localization of AR

▶ Optimal assay TBD◼ CTC based

◼ Plasma ddPCR for AR

amplification/mutation

ARV7: Not Yet Ready for Use in

Treatment Selection (cont.)

Conteduca et al, 2017.

Are CTC Counts Useful in Managing

Patients With Metastatic CRPC?

de Bono et al, 2008.

Single Sequential Remains

the Standard Paradigm

Attard et al, 2017.

Single Sequential Remains

the Standard Paradigm (cont.)

Attard et al, 2017.

Mr. JW (cont.)

▶ Abiraterone was discontinued

▶ Received docetaxel x 8 cycles with stable disease

▶ Upon PSA progression received enzalutamide ◼ A few months later radium-223 was added due to emerging

bone pain

▶ Now PSA is rising again. Patient has good

performance status and organ function

Non-AR Targeted Agents

Under Investigation

Agent(s) Target Select Population Phase of Trial

Niraparib, Olaparib,

Rucaparib, TalazoparibPARP

DNA repair deficient

or non-selected (in combinations)II and III

Cabozantinib VEGF, c-Met Unselected Ib/II (with ipi/nivo)

Palbociclib CDK4/6 Unselected II

Pembrolizumab PD-1 Progressing on enzalutamide II

Durvalumab ±

Tremelimumab

PD-L1

CTLA4Unselected II

Lu177-j591 PSMA Unselected II

MLN 8237 (alisertib) Aurora

KinaseSmall cell/neuroendocrine II

GSK525762 BET Progression on enza/abi Ib

LY2606368 Chk1/2 BRCA mutated I

Mateo et al, 2015; Ryan et al, 2017; Reinstein et al, 2017; Clinicaltrials.gov, 2017k; Graff et al, 2016a; Silvestri et al, 2016; Tagawa

et al, 2013; Graff et al, 2016b; Clinicaitrials.gov, 2017l; Clinicaltrials.gov, 2017m. Clinicaltrials.gov, 2017n.

DNA Repair Deficiency Predicts

Response to PARP Inhibitors

PARP = poly ADP ribose polymerase.

de Lartigue, 2013.

DNA Repair Deficiency Predicts

Response to PARP Inhibitors (cont.)

Mateo et al, 2015.

DNA Repair Deficiency Is Common in

Metastatic CRPC and Prognostic

Hussain et al, 2017; Pritchard et al, 2016.

Arm A: Abiraterone (n=31)

Arm B: Abiraterone + Veliparib (n=44)

Key Takeaways

▶ Single sequential treatment remains only strategy with

level 1 evidence◼ Combination trials underway/completed

▶ Imaging is important for monitoring treatment response◼ PSA rise alone usually not enough to indicate treatment

change

▶ No current biomarker to select patients for treatment◼ DNA repair deficiency may select for PARP inhibitor, common

in metastatic prostate cancer. Consider screening

◼ ARV7 assay needs validation before implementation

Key Takeaways (cont.)

▶ Future treatment may include immune checkpoint

inhibitors and/or PARP inhibitors

Consider referring for clinical trials early

given that combination trials with standard

agents are very common.

Audience Q&AsUse the Questions section of your Control Panel

to submit questions to the faculty.

To receive CME/CE credit visit:

www.i3health.com/CRPC

References

Antonarakis ES, Lu C, Chen Y, et al (2015). AR splice variant 7 (AR-V7) and response to taxanes in men with metastatic castration-resistant

prostate cancer (mCRPC). J Clin Oncol (2015 Genitourinary Cancers Symposium Abstracts), 33(suppl 7). Abstract 138.

Antonarakis ES, Lu C, Wang H, et al (2014). AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med,

371(11):1028-1038. DOI:10.1056/nejmoa1315815

Attard G, Borre M, Gurney H, et al (2017). A phase IV, randomized, double-blind, placebo (PBO)-controlled study of continued enzalutamide

(ENZA) post prostate-specific antigen (PSA) progression in men with chemotherapy-naive metastatic castration-resistant prostate

cancer (mCRPC). J Clin Oncol (ASCO Annual Meeting Abstracts), 35(uppl 15). Abstract 5004.

Beer TM, Armstrong AJ, Rathkopf DE, et al (2014). Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med,

371(5):424-433. DOI:10.1056/nejmoa1405095

Boron WF & Boulpaep EL (2003). In: Medical Physiology: A Cellular and Molecular Approach, Elsevier/Saunders.

Clinicaltrials.gov (2017a). Enzalutamide with or without abiraterone and prednisone in treating patients with castration-resistant metastatic

prostate cancer. NLM identifier: NCT01949337

Clinicaltrials.gov (2017b). A randomized phase IIa efficacy and safety study of radium-223 dichloride with abiraterone acetate or enzalutamide in

metastatic castration-resistant prostate cancer (CRPC). NLM identifier: NCT02034552

Clinicaltrials.gov (2017c). Phase III radium-223 mCRPC-PEACE III. NLM idenfifier: NCT02194842

Clinicaltrials.gov (2017d). Radium-223 dichloride and abiraterone acetate compared to placebo and abiraterone acetate for men with cancer of

the prostate when medical or surgical castration does not work and when the cancer has spread to the bone, has not been treated with

chemotherapy and is causing no or only mild symptoms (ERA 223). NLM identifier: NCT02043678

Clinicaltrials.gov (2017e). Multicenter trial of abiraterone acetate with or without cabazitaxel in treatment of metastatic castration resistant

prostate cancer. NLM identifier: NCT02218606

Clinicaltrials.gov (2017f). Ipatasertib plus abiraterone plus prednisone/prednisolone, relative to placebo plus abiraterone plus

prednisone/prednisolone in adult male patients with metastatic castrate-resistant prostate cancer (IPATential150). NLM identifier:

NCT03072238

Clinicaltrials.gov (2017g). A study of atezolizumab (anti-PD-L1 antibody) in combination with enzalutamide in participants with metastatic

castration-resistant prostate cancer (mCRPC) after failure of an androgen synthesis inhibitor and failure of, ineligibility for, or refusal of

a taxane regimen (IMbassador250). NLM identifier: NCT03016312

Clinicaltrials.gov (2017h). An efficacy and safety study of apalutamide (JNJ-56021927) in combination with abiraterone acetate and prednisone

versus abiraterone acetate and prednisone in participants with chemotherapy-naive metastatic castration-resistant prostate cancer

(mCRPC). NLM identifier: NCT02257736

References

Clinicaltrials.gov (2017i). Study evaluating the addition of pembrolizumab to radium-223 in mCRPC. NLM idenfier: NCT03093428

Clinicaltrials.gov (2017j). A study of galeterone compared to enzalutamide in men expression androgen receptor splice varian—7 mRNA (AR-

V7) metastatic CRPC (ARMOR3-SV). NLM identifier: NCT002438007

Clinicaltrials.gov (2017k). Cabozantinib-s-malate and nivolumab with or without ipilimumab in treating patients with metastatic genitourinary

tumors. NLM identifier: NCT02496208

Clinicaltrials.gov (2017l). Palbociclib in patients with metastatic castration-resistant prostate cancer. NLM identifier: NCT02905318

Clinicaltrials.gov (2017m). Dose escalation and dose expansion study of GSK525762 in combination with androgen deprivation therapy and

other agents in subjects with castrate-resistant prostate cancer. NLM identifier: NCT03150056

Clinicaltrials.gov (2017n). A phase II single arm pilot study of the ChL1/2 inhibitor (LY2606368) in BRCA1/2 mutation associated breast or

ovarian cancer, triple negative breast cancer, high grade serous ovarian cancer, and metastatic castrate-resistant prostate cancer. NLM

identifier: NCT02203513

Conteduca V, Wetterskog D, Sharabiani MTA, et al (2017). Androgen receptor gene status in plasma DNA associates with worse outcome on

enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study. Ann Onc, 28:1508-

1516. DOI:10.1093/annonc/mdx155

de Bono JS, Logothetis CJ, Molina A, et al (2011). Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med,

364(21):1995-2005. DOI:10.1056/nejmoa1014618

de Bono JS, Oudard S, Ozguroglu M, et al (2010). Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate

cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet, 376(9747):1147-1154. DOI:10.1016/s0140-

6736(10)61389-x

de Bono JS, Scher HI, Montgomery RB, et al (2008). Circulating tumor cells predict survival benefit from treatment in metastatic castration-

resistant prostate cancer. Clin Cancer Res, 14(19):6302-6309. DOI:10.1158/1078-0432.CCR-08-0872

de Lartigue J (2013). New life for PARP inhibitors: emerging agents leave mark at ASCO. OncLive. Available at:

http://www.onclive.com/publications/oncology-live/2013/august-2013/new-life-for-parp-inhibitors-emerging-agents-leave-mark-at-

asco?p=1

Graff JN, Alumkal JJ, Drake CG, et al (2016a). Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget,

7(33):52810-52817. DOI:10.18632/oncotarget.10547

Graff JN, Higano CS, Hahn NM, et al (2016b). Open-label, multicenter, phase 1 study of alisertib (MLN8237), an aurora A kinase inhibitor, with

docetaxel in patients with solid tumors. Cancer, 122(16):2524-2533. DOI:10.1002/cncr.30073

References

Grande E, Fernandez Perez MP, Font A, et al (2016). Early responses to enzalutamide in AR-V7 positive first line metastatic castration-resistant

prostate cancer (mCRPC). A prospective SOGUG clinical trial: the PREMIERE study. Ann Onc (ESMO 2016 Annual Meeting

Abstracts), 27(suppl 6). Abstract 726PD.

Higano CS, Schellhammer PF, Small EJ, et al (2009). Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of

active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer, 115(16):3670-3679. DOI:10.1002/cncr.24429

Hussain M, Daignault S, Twardowski P, et al (2017). Abiraterone + prednisone (Abi) +/- veliparib (Vel) for patients (pts) with metastatic

castration-resistant prostate cancer (CRPC): NCI 9012 updated clinical and genomics data. J Clin Oncol (ASCO Annual Meeting

Abstracts), 35. Abstract 5001.

Hussain M, Daignault S, Twardowski P, et al (2016). Co-targeting androgen receptor (AR) and DNA repair: a randomized ETS gene fusion-

stratified trial of abiraterone + prednisone (Abi) +/- the PARP1 inhibitor veliparib for metastatic castration-resistant prostate cancer

(mCRPC). J Clin Oncol (ASCO Annual Meeting Abstracts), 34. Abstract 5010.

Kantoff PW, Higano CS, Shore ND, et al (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med,

363(5):411-422. DOI:10.1056/nejmoa1001294

Loriot Y, Bianchini D, Ileana E, et al (2013). Antitumor activity of abiraterone acetate against metastatic castration-resistant prostate cancer

progressing after docetaxel and enzalutamide (MDV-3100). Ann Oncol, 24(7):1807-1812. DOI:10.1093/annonc/ndt136

Mateo J, Carreira S, Sandhu S, et al (2015). DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med, 373(18):1697-1708.

DOI:10.1056/nejmoa1506859

National Comprehensive Cancer Network (2017). NCCN Clinical Practice Guidelines in Oncology: prostate cancer. Version 2.2017. Available

at: http://www.nccn.org

Oudard S, Fizazi K, Sengeløv L, et al (2017). Cabazitaxel versus docetaxel as first-line therapy for patients with metastatic castration-resistant

prostate cancer: a randomized phase III trial-FIRSTANA. J Clin Oncol. [Epub ahead of print] DOI: 10.1200/JCO.2016.72.1068

Parker C, Nilsson S, Heinrich D, et al (2013). Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med, 369(3):213-

223. DOI:10.1056/nejmoa1213755

Petrylak DP, Tangen CM, Hussain MHA, et al (2004). Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced

refractory prostate cancer. N Engl J Med, 351(15):1513-1520. DOI:10.1056/nejmoa041318

Pritchard CC, Mateo J, Walsh MF, et al (2016). Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med,

374(5):443-453. DOI:10.1056/nejmoa1603144

References

Rathkopf DE, Smith MR, de Bono JS, et al (2014). Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic

castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol, 66(5):815-825.

DOI:10.1016/j.eururo.2014.02.056

Reichert Z, Carneiro BA, Daighnault-Newton S, et al (2017). A randomized phase II trial of abiraterone, olaparib, or abiraterone + olaparib in

patients with metastatic castration-resistant prostate cancer with DNA repair defects. J Clin Oncol, 35(15_suppl).

DOI:10.1200/JCO.2017.35.15_suppl.TPS5086

Schellhammer PF, Chodak G, Whitemore JB, et al (2013). Lower baseline prostate-specific antigen is associated with a greater overall survival

benefit from sipuleucel-T in the immunotherapy for prostate adenocarcinoma treatment (IMPACT) trial. Urology, 81(6):1297-1302.

DOI:10.1016/j.urology.2013.01.061

Scher HI, Fizazi K, Saad F, et al (2012). Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med,

367(13):1187-1197. DOI:10.1056/nejmoa1207506

Scher HI, Graf RP, Schreiber NA et al (2017). Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic

castration-resistant prostate cancer. Eur Urol, 71(6):874-882. DOI:10.1016/j.eururo.2016.11.024

Scher HI, Morris MJ, Stadler WM, et al (2016). Trial design and objectives for castration-resistant prostate cancer: updated recommendations

from the prostate cancer clinical trials working group 3. J Clin Oncol, 34(12):1402-1418. DOI:10.1200/jco.2015.64.2702

Silvestri I, Cattarino S, Giantulli S, et al (2016). A perspective of immunotherapy for prostate cancer. Cancers (Basel), 8(7):64.

DOI:10.3390/cancers8070064

Suzman DL, Luber B, Schweizer MT, et al (2014). Clinical activity of enzalutamide versus docetaxel in men with castration-resistant prostate

cancer progressing after abiraterone. Prostate, 74(13):1278-1285. DOI:10.1002/pros22844

Tagawa ST, Milowsky MI, Morris M, et al (2013). Phase II study of Lutetium-177-labeled anti-prostate-specific membrane antigen monoclonal

antibody J591 for metastatic castration-resistant prostate cancer. Clin Cancer Res, 19(18):5182-5191. DOI:10.1158/1078-0432.CCR-

13-0231

Tannock IF, de Wit R, Berry WR, et al (2004). Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl

J Med, 351(15):1502-1512. DOI:10.1056/nejmoa040720

Watson PA, Arora VK & Sawyers CL (2015). Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev

Cancer, 15(12):701-711. DOI:10.1038/nrc4016