This document summarizes several androgen receptor-targeted agents (apalutamide, enzalutamide, darolutamide) approved for treatment of prostate cancer, including their indications, dosing, and common adverse events. It also describes ongoing clinical trials evaluating these and other agents (PARP inhibitors, immunotherapy) alone or in combination for metastatic castration-sensitive, non-metastatic castration-resistant, and metastatic castration-resistant prostate cancer. Many trials are investigating these novel approaches in patients with DNA damage repair defects.

1. Access the activity, “Mapping the Pathways to Better Patient Outcomes in Prostate Cancer: Personal
Insights and Guidance From the Patient CaseBook” at PeerView.com/SEP40
AR-Targeted Agents in Prostate Cancer
PRACTICE AID
Indication
• Patients with metastatic CSPC and nmCRPC
Dosing
• 240 mg orally once daily; swallow whole with
or without food
• Should also receive a GnRH analog concurrently
or have had a bilateral orchiectomy
AEs in ≥10% of Patients
• Fatigue, arthralgia, rash, decreased appetite,
falls, weight decrease, hypertension, hot flush,
diarrhea, and fracture
Indication
• Patients with CRPC and metastatic CSPC
AEs in ≥10% of Patients
• Asthenia/fatigue, back pain, hot flush,
constipation, arthralgia, decreased appetite,
diarrhea, and hypertension
Dosing
• 160 mg orally once daily; swallow whole with
or without food
• Should also receive a GnRH analog concurrently
or have had a bilateral orchiectomy
Apalutamide EnzalutamideDarolutamide
Indication
• Patients with nmCRPC
Dosing
• Two 300-mg tablets administered orally twice
daily; taken with food
• Should also receive a GnRH analog concurrently
or have had a bilateral orchiectomy
AEs in ≥2% of Patients
• Fatigue, pain in extremity, and rash
Indication, Dosing, and AEs in AR-Targeted Agents for Prostate Cancer1-3

2. Access the activity, “Mapping the Pathways to Better Patient Outcomes in Prostate Cancer: Personal
Insights and Guidance From the Patient CaseBook” at PeerView.com/SEP40
AR-Targeted Agents in Prostate Cancer
PRACTICE AID
a
OS not reached in apalutamide or placebo groups as of May 15, 2019.
ADT: androgen deprivation therapy; AE: adverse event; AR: androgen receptor; CRPC: castration-resistant prostate cancer; CSPC: castration-sensitive prostate cancer; CT: computed tomography; ECOG PS: Eastern Cooperative Oncology Group Performance Status; GnRH: gonadotropin-
releasing hormone; HSPC: hormone-sensitive prostate cancer; MFS: metastasis-free survival; mHSPC: metastatic hormone-sensitive prostate cancer; nmCRPC: nonmetastatic castration-resistant prostate cancer; PSA: prostate-specific antigen; PSADT: prostate-specific antigen
doubling time; rPFS: radiographic progression-free survival.
1. Erleada (apalutamide) Prescribing Information. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/ERLEADA-pi.pdf. Accessed January 28, 2020. 2. Xtandi (enzalutamide) Prescribing Information. https://www.astellas.us/docs/12A005-ENZ-
WPI.PDF. Accessed January 28, 2020. 3. Nubeqa (darolutamide) Prescribing Information. http://labeling.bayerhealthcare.com/html/products/pi/Nubeqa_PI.pdf. Accessed January 28, 2020. 4. Small EJ et al. Ann Oncol. 2019;30:1813-1820. 5. Smith MR et al. N Engl J Med. 2018;378:1408-
1418. 6. Hussain M et al. N Engl J Med. 2018;378:2465-2474. 7. Fizazi K et al. American Society of Clinical Oncology 2019 Genitourinary Cancers Symposium (ASCO GU 2019). Abstract 140. 8. Chi KN et al. 2019 American Society of Clinical Oncology Annual Meeting (ASCO 2019). Abstract
5006. 9. https://clinicaltrials.gov/ct2/show/NCT02489318. Accessed January 28, 2020. 10. https://clinicaltrials.gov/ct2/show/NCT02677896. Accessed January 28, 2020. 11. Armstrong AJ et al. ASCO GU 2019. Abstract 687. 12. https://www.ascopost.com/issues/april-10-2019-supplement-
conference-highlights-gugi-2019/interim-analysis-of-the-arches-trial/. Accessed January 28, 2020. 13. https://clinicaltrials.gov/ct2/show/NCT02799602. Accessed January 28, 2020.
• nmCRPC
• Rising PSA despite castrate testosterone level (≤50 ng/dL)
• PSADT ≤10 mo
Apalutamide
40.5 mo
Placebo
16.2 mo
1° endpoint:
MFS
vs
MFS
SPARTAN
Apalutamide
+ ADT
Placebo
+ ADT
• nmCRPC
• Rising PSA despite castrate testosterone level (≤50 ng/dL)
• Baseline PSA ≥2 ng/mL; PSADT ≤10 mo
Enzalutamide
36.6 mo
Placebo
14.7 mo
1° endpoint:
MFS
vs
MFS
PROSPER
Enzalutamide
+ ADT
Placebo
+ ADT
• nmCRPC
• Castrate level of serum testosterone (<50 ng/dL)
• Baseline PSA ≥2 ng/mL; PSADT ≤10 mo
Darolutamide
40.4 mo
Placebo
18.4 mo
1° endpoint:
MFS
vs
MFS
ARAMIS
Darolutamide
+ ADT
Placebo
+ ADT
AR-Targeted Agents in Nonmetastatic CRPC4-7
• mHSPC
• Newly diagnosed or previously treated
• ECOG PS 0 or 1
Apalutamide
Not Reached
Enzalutamide
Not Reached
Placebo
21.1 mo
1° endpoint:
Median rPFS
and OSa
vs
rPFS
TITAN
Apalutamide
+ ADT
Placebo
+ ADT
• mHSPC (confirmed by bone scan, CT, or MRI)
• ECOG PS 0 or 1
Placebo
19.45 mo
1° endpoint:
rPFS
vs
rPFS
ARCHES
Enzalutamide
+ ADT
Placebo
+ ADT
• mHSPC
• Newly diagnosed
• ECOG PS 0 or 1
1° endpoint:
OS
vs
ARASENS
Darolutamide
+ ADT
+ docetaxel
Placebo
+ ADT
+ docetaxel
AR-Targeted Agents in Metastatic HSPC8-13
Ongoing; primary completion date:
August 2022

3. Novel Approaches in
Advanced Prostate Cancer
PRACTICE AID
Access the activity, “Mapping the Pathways to Better Patient Outcomes in Prostate Cancer: Personal
Insights and Guidance From the Patient CaseBook” at PeerView.com/SEP40
TOPARP-B (NCT01682772);
Multi-stage phase 2 design
RESULTS
• mCRPC; ongoing ADT or prior bilateral orchiectomy
• Previously treated with 1 or 2 lines of taxane-based
chemo and/or AR-directed therapy
• N = 98
PROfound (NCT02987543); Phase 3
• mCRPC; ongoing ADT or prior
bilateral orchiectomy
• Previously treated with AR-targeted therapy
• N = 387
RR; evaluable N = 98
Endpoints:
ORR 54% in 400 mg, 37% in 300 mg olaparib cohort
Median PFS: 5.4 mo
Primary endpoint per gene subgroup:
BRCA1/2: 80%
PALB2: 57%
RESULTS
Olaparib: median rPFS 7.39 mo
Physician's choice: rPFS 3.55 mo
HR = 0.34 (95% CI, 0.25-0.47);
P < .0001
Olaparib 1° endpoint: RR
1° endpoint:
rPFS
Olaparib
+ abiraterone
Placebo
+ abiraterone
vs vs
1° endpoint:
rPFS
Galahad (NCT02854436); Phase 2
RESULTS
RESULTS
• mCRPC previously treated with
≥1 line of taxane-based chemo;
received ≥1 line of AR-targeted
therapy
• DDR anomalies
• Planned N = 301
N = 81 (46 with BRCA1/2
and 35 with non-BRCA1/2)
ORR
41% in BRCA1/2; 9% in non-BRCA1/2
Composite response rate
63% in BRCA1/2; 17% in BRCA1/2
PSA response rate
50% in BRCA1/2; 3% in non-BRCA1/2
Niraparib 1° endpoint: ORR
TRITON2 (NCT02952534); Phase 2
• mCRPC; progression on AR-directed
therapy and 1 prior taxane;
HRR gene aberration
• No prior PARP inhibitor, mitoxantrone,
cyclophosphamide, or platinum-based
chemo
• Planned N = 360
ORR
BRCA1/2 pts, n = 69: 47.5%
PSA response
BRCA1/2 pts, n = 69: 53.6%
Rucaparib 1° endpoints: ORR, PSA response
Selected Ongoing Trials of PARP Inhibitors1-6
ATM: 37%
CDK12: 25%
NCT01972217; Phase 2
RESULTS
• mCRPC
• ECOG PS 0 or 1
• ≤2 prior lines of chemo
• Planned N = 158
rPFS; evaluable N = 142
Olaparib: 13.8 mo
Placebo: 8.2 mo
HR = 0.65; P = .034
Enzalutamide
or abiraterone
Olaparib

4. Novel Approaches in
Advanced Prostate Cancer
PRACTICE AID
Access the activity, “Mapping the Pathways to Better Patient Outcomes in Prostate Cancer: Personal
Insights and Guidance From the Patient CaseBook” at PeerView.com/SEP40
Talazoparib
+ enzalutamide
vs 1° endpoints:
dose, rPFS
Placebo
+ enzalutamide
Selected Ongoing Trials of PARP Inhibitors1
(Cont’d)
PROpel (NCT03732820); Phase 3
• mCRPC; ongoing ADT or prior bilateral orchiectomy
• ECOG PS 0 or 1
• Assessment of HRR gene aberrations
• Planned N = 720
vs 1° endpoint:
rPFS
Placebo
+ abiraterone
Olaparib
+ abiraterone
vs 1° endpoint:
rPFS
Placebo
+ abiraterone
Olaparib
+ abiraterone
MAGNITUDE (NCT03748641); Phase 3
• mCRPC; ongoing ADT or prior bilateral orchiectomy
• Planned N = 1,000
TRITON3 (NCT02975934); Phase 3
• mCRPC previously treated with 1 next-generation
AR-targeted therapy
• Deleterious mutation in BRCA1/2 or ATM
• Planned N = 400
vs
1° endpoint:
rPFS
Abiraterone
or enzalutamide
or docetaxel
Rucaparib
Avelumab +
bempegaldesleukin
Recruiting Recruiting Recruiting
Recruiting Recruiting
Rucaparib 1° endpoint:
ORR
1° endpoints:
confirmed OR,
PSA response, DLTs
LODESTAR (NCT04171700); Phase 2, open-label
• Unresectable, locally advanced, or metastatic solid tumor and relapsed/progressive disease
• At least 1 prior line of therapy extending OS or SOC therapy for advanced disease
• mCRPC with BRCA1/2 mutations
• ECOG PS 0 or 1
• Planned N = 220 (with solid tumors)
Avelumab + bempegaldesleukin (NKTR-214) + talazoparib or
enzalutamide (NCT04052204); Phase 2, open-label
• mCRPC
• ECOG PS 0 or 1
• Planned N = 160
• Cohort A: deleterious mutations in BRACA1/2
• Cohort B: non-BRACA1/2 mutations
• Combination B: mCRPC with
DDR defect: + talazoparib
• Combination C: + enzalutamide
Recruiting Recruiting
Talazoparib 1° endpoint:
ORR
TALAPRO-1 (NCT03148795); Phase 2, open-label
• mCRPC; metastatic disease in bone
• Assessment of DDR mutation status
• ECOG PS 0 to 2
• Planned N = 100
TALAPRO-2 (NCT03395197); Phase 3
• mCRPC; metastatic disease
in bone
• Assessment of DDR mutation status
• ECOG PS 0 or 1
• Planned N = 1,037

5. Novel Approaches in
Advanced Prostate Cancer
PRACTICE AID
Access the activity, “Mapping the Pathways to Better Patient Outcomes in Prostate Cancer: Personal
Insights and Guidance From the Patient CaseBook” at PeerView.com/SEP40
Selected Ongoing Trials of PARP Inhibitors Combined With PD-1/PD-L1 Inhibitors1,7-10
JAVELIN PARP MEDLEY
(NCT03330405); Phase 2
• Locally advanced or mCRPC
• Primary or metastatic tumor biopsy
• ECOG PS 0 or 1
• Planned N = 242
CheckMate -9KD (NCT03338790);
Phase 2
• mCRPC; ongoing ADT
• Plasma and fresh or
archival tumor tissue
• ECOG PS 0-1
CheckMate -7DX
(NCT04100018); Phase 3
• Stage IV prostate cancer
• ECOG PS 0-1
• Ongoing ADT
• Chemotherapy-naïve and received 1-2 prior
second-generation hormonal therapies
Recruiting Recruiting Recruiting
1° endpoints:
DLTs, OR
1° endpoints:
safety, ORR,
composite RR
• HRD status (must be
available before tx
arm assignment)
• Planned N = 330
1° endpoints:
ORR, PSA response
• Planned
N = 984
1° endpoints:
rPFS, OS
Nivolumab or placebo
+ docetaxel in CRPC
Avelumab +
talazoparib
Nivolumab + rucaparib or
docetaxel or enzalutamide
KEYNOTE-365 (NCT02861573);
Phase 1b/2
• mCRPC; ongoing ADT
• Tissue biopsy from site not previously irradiated
• Planned N = 400
QUEST (NCT03431350);
Phase 1/2
• mCRPC
• DDR gene anomalies
• Prior novel AR-targeted therapy
• Planned N = 80
NCT02484404;
Phase 2 (prostate cohort)
• mCRPC; ongoing ADT or prior bilateral orchiectomy
• ECOG PS 0 or 1; previously treated with enzalutamide
and/or abiraterone
• Planned N = 384
Recruiting
Niraparib
+ cetrelimab
RESULTS
PSA response
Pembro + olaparib, n = 41: 12%
Pembro + docetaxel, n = 72: 31%
Pembro + enzalutamide, n = 69: 27%
1° endpoint:
PSA response
Pembrolizumab + olaparib
or docetaxel/prednisone or
enzalutamide or abiraterone 1° endpoints:
dose, safety
Durvalumab
+ olaparib
RESULTS
rPFS; evaluable N = 17
Durvalumab + olaparib: 16.1 mo
12-month rPFS: 51.5%
9/17 (53%) patients had a radiographic and/or
PSA response
ADT: androgen deprivation therapy; AR: androgen receptor; DDR: DNA damage repair; DLT: dose-limiting toxicity; ECOG PS: Eastern Cooperative Oncology Group Performance Status; HRD: homologous recombination deficiency; HRR: homologous recombination repair;
mCRPC: metastatic castration-resistant prostate cancer; OR: overall response; ORR: objective response rate; PARP: poly (ADP-ribose) polymerase; PD-1: programmed cell death protein 1; PD-L1: programmed death ligand 1; PSA: prostate-specific antigen; rPFS: radiographic
progression-free survival ; RR: response rate.
1. https://clinicaltrials.gov. Accessed January 28, 2020. 2. Mateo J et al. 2019 American Society of Clinical Oncology Annual Meeting (ASCO 2019). Abstract 5005. 3. Clarke N et al. Lancet Oncol. 2018;19:975-986. 4. Hussain M et al. European Society for Medical Oncology Congress
2019 (ESMO 2019). Abstract LBA12_PR. 5. Abida W et al. ESMO 2019. Abstract 846PD. 6. Smith MR et al. American Society of Clinical Oncology 2019 Genitourinary Cancers Symposium (ASCO GU 2019). Abstract 202. 7. Yu EY et al. J Clin Oncol. 37;2019. Abstract 5027. 8. Massard C et al.
J Clin Oncol. 37;2019. Abstract 5029. 9. Fong P et al. J Clin Oncol. 37;2019. Abstract 5010. 10. Karzai F et al. J Immunother Cancer. 2018;6:141.

6. Improving Patient Outcomes
in Prostate Cancer: A Patient
CaseBook for Physicians
Access the activity, “Mapping the Pathways to Better Patient Outcomes in
Prostate Cancer: Personal Insights and Guidance From the Patient CaseBook”
at PeerView.com/SEP40
PRACTICE AID
Case 1
63-Year-Old ManWith nmCRPC
• pT3bN0 Gleason 4+3 prostate cancer s/p prostatectomy (2013) and salvage
radiation therapy (2015)
• Has been on salvage ADT since 2016
– Pretreatment PSA: 12.7 ng/mL; PSA nadir: <0.10 ng/mL
• Latest PSA: 2.7 ng/mL; PSADT: 5 months
• Bone scan and abdominal-pelvic CT with no detectable metastases
 Diagnosis: Nonmetastatic castration-resistant prostate cancer
 Next Steps: Start one of the novel AR inhibitors (apalutamide, enzalutamide,
or darolutamide)
Case 2
59-Year-Old ManWith CRPC
• pT3aN1 prostate cancer, Gleason 4+5
• Post-operative PSA elevated at 2.3 ng/mL
• Has been on salvage ADT for the last 5 years
– PSA nadir: <0.10 ng/mL
• Latest PSA: 5.7 ng/mL; PSADT: 4.9 months
• Bone scan and abdominal-pelvic CT with no detectable metastases
• PSMA PET-CT with multiple subcentimeter PSMA-avid nodes (para-aortic,
mediastinal, and left supraclavicular)
 Diagnosis: Nonmetastatic castration-resistant prostate cancer
(Bone scan and abdominal pelvic CT showed no detectable metastases,
so by the definitions of the trials he would be nmCRPC)
 Next Steps: Start one of the novel AR inhibitors (apalutamide, enzalutamide,
or darolutamide). SPARTAN, PROSPER, and ARAMIS trials actually provide the
best evidence for treating patients with CRPC and metastases that are detectable
only by sensitive next-generation imaging modalities

7. Improving Patient Outcomes
in Prostate Cancer: A Patient
CaseBook for Physicians
Access the activity, “Mapping the Pathways to Better Patient Outcomes in
Prostate Cancer: Personal Insights and Guidance From the Patient CaseBook”
at PeerView.com/SEP40
PRACTICE AID
Case 3
69-Year-Old ManWith mCSPC
• Presents with urinary obstructive symptoms
• Past medical history: Diabetes for 15 years, well controlled on metformin
• Family history: Father and brother with history of prostate cancer
• Examination: Enlarged nodular prostate on rectal exam
• Labs: Elevated PSA (25 ng/mL)
• Prostate biopsy: Adenocarcinoma of prostate, Gleason 4+4
• CT abdomen and pelvis: Enlargement of multiple retroperitoneal lymph nodes
• Bone scan: 2 osteoblastic lesions (T4, T9 vertebral body lesions)
 Diagnosis: Metastatic castration-sensitive prostate cancer
(low volume/low risk)
For
Refill times
Date
What would you recommend for this patient?
• Treatment: Bicalutamide 50 mg daily x 2 weeks and leuprolide 22.5 mg IM
started the same day. Pre-authorization for abiraterone + prednisone started
• 1-month follow-up: Abiraterone 1,000 mg + prednisone 5 mg daily started
• 2-month follow-up: Mild fatigue, right upper quadrant discomfort
• Vitals: BP 155/95 mmHg
• Labs: Elevated liver enzymes (ALT: 550 units/L; AST: 500 units/L)
 Diagnosis: Liver toxicity and hypertension due to abiraterone
 Next Steps: Abiraterone discontinued; apalutamdide 240 mg daily started

8. Improving Patient Outcomes
in Prostate Cancer: A Patient
CaseBook for Physicians
Access the activity, “Mapping the Pathways to Better Patient Outcomes in
Prostate Cancer: Personal Insights and Guidance From the Patient CaseBook”
at PeerView.com/SEP40
PRACTICE AID
Case 4
65-Year-Old ManWith mCSPC
• Presents to ED with right hip/right lower quadrant pain
• Past medical history: Hypertension, diabetes, currently not on any medications
• Exam: Decreased movement in the right hip
• CT scan of the abdomen and pelvis: Impending pathologic fracture in the right
femur shaft; multiple sclerotic bone lesion in the right and left femur;
retroperitoneal lymadenopathy
• Bone scan: Widespread osteoblastic bone metastasis (>25 bone lesions)
• Serum PSA level: 550 ng/mL
• Prostate biopsy: Prostate adenocarcinoma, Gleason score 5+4
 Diagnosis: Metastatic castration-sensitive prostate cancer
(high volume/ high risk)
For
Refill times
Date
What would you recommend for this patient?
 Treatment: Bicalutamide 50 mg daily for 4 weeks, leuprolide 22.5 mg IM
2 weeks into bicalutamide. Docetaxel is started on the day of completion of
bicalutamide every 3 weeks x 6. Leuprolide is continued every 3 months
 6-month follow-up: Mild fatigue; tingling and numbness in fingertips and toes
(mild sensory neuropathy); PSA: 0.4 ng/mL; patient asks about the role of adding
enzalutamide or apalutamide to treatment

9. Improving Patient Outcomes
in Prostate Cancer: A Patient
CaseBook for Physicians
Access the activity, “Mapping the Pathways to Better Patient Outcomes in
Prostate Cancer: Personal Insights and Guidance From the Patient CaseBook”
at PeerView.com/SEP40
PRACTICE AID
Case 5
58-Year-Old ManWith mCRPC
• Presents for second opinion with widespread mCRPC
• Received all FDA-approved agents that prolong survival for mCRPC;
still has an ECOG PS of 1
• Hoping for clinical trial options
• Upon taking a family history, you find out he has a significant family history
of cancer, with 3 women on his mother’s side who died at a young age from
breast cancer
Patient: Prostate Cancer Family History of Breast Cancer
Died car
accident
Died car
accident
Died car
accident
Died car
accident
Prostate
cancer
Dx 58
Prostate
cancer
Dx 58
Died (35 y)
breast
cancer
Died (33 y)
breast
cancer
Died
breast
cancer

10. Improving Patient Outcomes
in Prostate Cancer: A Patient
CaseBook for Physicians
Access the activity, “Mapping the Pathways to Better Patient Outcomes in
Prostate Cancer: Personal Insights and Guidance From the Patient CaseBook”
at PeerView.com/SEP40
PRACTICE AID
Recommended Screening for Risk Reduction
Died car
accident
Referred patient's
daughter to
breast/ovarian
prevention clinic,
had RRO
Referred patient's
nephews for
prostate cancer
screening
Prostate
cancer
Dx 58
Died car
accident
Died
(35 y)
breast
cancer
Died
(33 y)
breast
cancer
Died
breast
cancer
For
Refill times
Date
What should you consider now?
 Germline DNA repair gene testing
 Microsatellite instability testing
 Somatic tumor testing with next-generation sequencing
 Referral to a genetic counselor
ADT: androgen deprivation therapy; AR: androgen receptor; CRPC: castration-resistant prostate cancer; ECOG PS: Eastern Cooperative Oncology Group Performance Status; ED: emergency department;
mCRPC: metastatic castration-resistant prostate cancer; mCSPC: metastatic castration-sensitive prostate cancer; nmCRPC: nonmetastatic castration-resistant prostate cancer; PSA: prostate-specific
antigen; PSADT: prostate-specific antigen doubling time; PSMA: prostate-specific membrane antigen.