Oncology Conference Evolving Options in Metastatic Prostate Cancer - - PowerPoint PPT Presentation

2020 Spring Oncology Conference

Evolving Options in Metastatic Prostate Cancer

3

• Implement guideline-recommended treatment strategies for patients with nonmetastatic

castrate-resistant prostate cancer (CRPC)

• Formulate personalized management strategies for patients with metastatic CRPC based
• n patient preferences and efficacy and safety of novel agents
• Apply strategies to identify and manage AEs associated with novel therapies for CRPC

Learning Objectives

AE = adverse event.

4

• Estimated for 2020

‒ 191,930 new cases ‒ 33,330 deaths ‒ Incidence and mortality rates have declined ‒ 10-year overall survival (OS): 98%

• Risk factors

‒ Advancing age ‒ African ancestry ‒ Family history ‒ Genetic mutations

Prostate Cancer in 2020

American Cancer Society. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and- figures/2020/cancer-facts-and-figures-2020.pdf. Accessed Mar 24, 2020.

Image: Histology slide showing prostate cancer. Courtesy of the National Cancer Institute. Photographer: Otis Brawley,

5

Advances in Treatment Approvals

mHSPC = metastatic hormone-sensitive prostate cancer; nmCRPC = nonmetastatic castrate-resistant prostate cancer. Komura K, et al. Int J Urol. 2018;25:220-231; US Food and Drug Administration. www.fda.gov/newsevents/newsroom/pressannouncements/ucm596768.htm. Accessed Mar 24, 2020; US Food and Drug Administration. www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=210951. Accessed Mar 24, 2020. US Food and Drug

• Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer.

Accessed Mar 24, 2020; US Food and Drug Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide- metastatic-castration-sensitive-prostate-cancer. Accessed Mar 24, 2020.

2004 2010 2011 2012 2013 2014 2018 2019

Docetaxel (taxane) Sipuleucel-T (immunotherapy) Cabazitaxel (novel taxane) Abiraterone (next- generation ARSI) postdocetaxel Enzalutamide (next- generation ARSI) postdocetaxel Radium-223 (radiopharmaceutical) Abiraterone predocetaxel Enzalutamide predocetaxel Apalutamide (next- generation ARSI) for nmCRPC Enzalutamide for nmCRPC Darolutamide (next-generation ARSI) for nmCRPC Enzalutamide for mHSPC

6

CHAARTED: ADT + Docetaxel in mHSPC

ADT = androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen. Sweeney CJ, et al. N Engl J Med. 2015;373:737-746. 12 24 36 48 60 72 Number at Risk ADT + docetaxel 397 333 189 89 46 5 2 ADT alone 393 318 168 71 27 3 1 84 100 80 60 40 20

OS (%)

ADT + docetaxel: (median OS, 57.6 months) ADT alone (n = 393): (median OS, 44.0 months) Death with ADT + docetaxel (n = 397): HR, 0.61 (95% CI, 0.47-0.80) P <.001

All Patients

OS Benefit by Volume of Disease

• High volume: 17 months
• Low volume: no benefit

Median follow-up: 28.9 months

7

STAMPEDE, Arm C: ADT and Docetaxel in HSPC

James ND, et al. Lancet. 2016;387:1163-1177. 10 20 30 40 50 60 70 80 90 Median OS Median OS Metastatic

Median OS (Months)

ADT Alone ADT + Docetaxel

71 Months

60 Months

0% 10% 20% 30% 40% 50% 60% 70% 5-Year Survival (Metastatic) 5-Year Survival

5-Year Survival (%)

ADT Alone ADT + Docetaxel

45 Months 81 Months 39% 55% 50% 63%

ADT alone: n = 1184 ADT + docetaxel: n = 592 Median follow-up: 43 months

8

Phase 3 Trials of ADT + Abiraterone in mHSPC

PFS = progression-free survival; rPFS = radiographic progression-free survival. Fizazi K, et al. N Engl J Med. 2017;377:352-360; James ND, et al. N Engl J Med. 2017;377:338-351.

N = 1199: ADT + abiraterone + prednisone vs ADT + placebo

LATITUDE

ADT + abiraterone HR, 0.29 (95% CI, 0.25-0.34) P <.001

PFS (%)

ADT

Months

100 80 60 40 20 6 12 18 24 30 36 42 48 54

STAMPEDE, Arm G

N = 960: ADT + abiraterone + prednisolone vs ADT alone

8 16 24 32 40 100 80 60 40 20

Months

Abiraterone Placebo HR, 0.47 (95% CI, 0.39-0.55) P <.001

rPFS (%)

9

Some Agents Used in Advanced Settings Are Now Being Used in Earlier Disease

Armstrong AJ, et al. J Clin Oncol. 2019;37(7 suppl):Abstract 687; Chi KN et al. J Clin Oncol. 2019;37(15 suppl):Abstract 5003; US Food and Drug

• Administration. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-metastatic-castration-sensitive-prostate-
• cancer. Accessed Mar 24, 2020.

ADT + apalutamide vs ADT + placebo in mHSPC rPFS: significant improvement in both low- and high-volume disease (P <.001) with apalutamide ADT + enzalutamide vs ADT + placebo in mHSPC PFS: significant improvement in both low- and high-volume disease (P <.001) with enzalutamide TITAN Phase 3 Study (N >1050) ARCHES Phase 3 Study (N = 1150)

10

NCCN = National Comprehensive Cancer Network. NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020.

2019 NCCN Guidelines for mHSPC

• Based on results of clinical trials, for patients with mHSPC, consider adding

to ADT: ‒ Docetaxel 75 mg/m2 every 3 weeks for 6 cycles

• Patients with high-volume disease derive greater benefit

‒ Abiraterone acetate + steroid ‒ Apalutamide ‒ Enzalutamide

11

• Disease progression despite castrate levels of testosterone (<50 ng/mL)
• Heterogeneous—can be symptomatic or asymptomatic, with or without

metastases

• Affects 10% to 20% of men with prostate cancer within 5 years of diagnosis

‒ Before recent therapeutic advances, ≥50% of these patients would have died within 3 years

• Natural history can involve progressive decline in health-related QoL
• Metastasis-free survival (MFS) is a new, reasonable endpoint for both

clinical trials and clinical discussions with patients

Castrate-Resistant Prostate Cancer

QoL = quality of life. Anantharaman A, et al. Expert Rev Anticancer Ther. 2017;17:625-633; Beaver JA, et al. N Engl J Med. 2018;378:2458-2460; Nussbaum N, et al. Prostate Cancer Prostatic Dis. 2016;19:111-121.

12

Typical Progression of CRPC

Adapted with permission from Anantharaman A, et al. Expert Rev Anticancer Ther. 2017;17:625-633.

Localized/locally advanced prostate cancer Definitive therapy Biochemical recurrence mHSPC mCRPC nmCRPC

Rising PSA Start ADT Criterion 2: Rising PSA despite castrate levels of testosterone Criterion 1: Identification of metastases Rising PSA despite castrate levels of testosterone Identification of metastases Both criteria met

13

• CRPC with no clinical or radiologic evidence of metastases
• Newer imaging techniques have greater sensitivity (eg, 18F-fluorocholine
• r PSMA-targeted PET)

‒ May reveal metastases earlier

• PSA testing every 4 to 6 months is advised
• Treatment is recommended for men with PSADT ≤10 months
• Until recently, no approved drugs were available for nmCRPC

Nonmetastatic CRPC

Image from Singh A, et al. PET Clin. 2017;12:193-203. PET = positron emission tomography; PSADT = prostate-specific antigen doubling time; PSMA = prostate-specific membrane antigen. Anantaraman A, et al. Expert Rev Anticancer Ther. 2017;17:625-633; Virgo KS, et al. J Clin Oncol. 2017;35:1952-1964; Zimmerman ME, et al. Clin Adv Hematol Oncol. 2019;17:455-463.

14

Case Study 1: Earl, 69 Years Old

• Earl has mild COPD and occasional arrhythmias

‒ No family history of cancer

• He underwent radiotherapy for localized prostate cancer 4 years ago
• Earl experienced biochemical recurrence as evidenced by increasing PSA
• Because of previous radiotherapy, he was not considered a candidate for surgery
• He was started on ADT 1 year ago

15

Case Study (cont’d): Earl’s Test Results

• PSA increased from 6 ng/mL to 14 ng/mL, with PSADT of 8 months

‒ Testosterone level: 23 ng/dL ‒ No evidence of metastases on CT or bone scan, no bone pain ‒ No lymph node masses detected

• Now diagnosed with nmCRPC

16

Patient Disease Treatment

• Preferences
• Medical history,

comorbidities, medications

• Treatment and response

history

• Symptoms
• Overall condition and

performance status

• Metastatic?

– To bone? – Visceral?

• Disease volume

– Low or high?

• Risk level/aggressiveness
• Toxicity profile
• Possible drug-drug

interactions

• Effects on pain, QoL
• Practitioner experience

and preference

Factors to Consider When Selecting Therapies

Basch E, et al. J Clin Oncol. 2014;32:3436-3448; Crawford ED, et al. J Urol. 2015;194:1537-1547; Nussbaum N, et al. Prostate Cancer Prostatic

• Dis. 2016;19:111-121; Zarrabi K, et al. J Hematol Oncol. 2019;12:89.

17

Fennimore LA, Ginex PK. Nurs Clin North Am. 2017;52:115-131; Makarov DV, et al. www.auanet.org/guidelines/shared-decision-making. Accessed Mar 24, 2020.

Shared Decision-Making

• Especially important for complex diseases such as CRPC
• Endorsed by all major guidelines
• Patients and clinicians collaborate on treatment selection
• May enhance adherence to therapies
• May improve outcomes: Greater adherence → better treatment responses

18

SPARTAN and PROSPER: Grade ≥3 AEs Occurring in >1% of Patients

NR = not reported. Hussain M, et al. N Engl J Med. 2018;378:2465-2474; Smith MR, et al. N Engl J Med. 2018;378:1408-1418.

AE SPARTAN PROSPER Apalutamide + ADT Placebo + ADT Enzalutamide + ADT Placebo + ADT Any grade ≥3 AE 362 (45.1%) 136 (34.2%) 292 (31%) 109 (23%) Hypertension 115 (14.3%) 47 (11.8%) 43 (5%) 10 (2%) Rash 42 (5.2%) 1 (0.3%) NR NR Fracture 22 (2.7%) 3 (0.8%) NR NR Falls 14 (1.7%) 3 (0.8%) 12 (1%) 3 (1%) Fatigue 7 (0.9%) 1 (0.3%) 27 (3%) 3 (1%) Hematuria NR NR 16 (2%) 13 (3%)

19

AEs (≥5% or grade ≥3) were similar between groups and included:

• Fatigue
• Back pain
• Arthralgia
• Diarrhea
• Hypertension
• Constipation

ARAMIS: Darolutamide in nmCRPC

Fizazi K, et al. N Engl J Med. 2019;380:1235-1246.

HR, 0.41 (95% CI, 0.34-0.50) P <.001

Darolutamide: 40.4 months (median) Placebo: 18.4 months (median)

Median follow-up time at primary analysis: 17.9 months

Probability of Survival Without Metastasis Months

0 4 8 12 16 20 24 28 32 36 40 44 48 1.0 0.8 0.6 0.4 0.2 0.0

Phase 3, placebo-controlled trial; N = 1509 (PSADT ≤10 months)

Risk of metastasis or death from any cause was reduced by 59%

20

2019 NCCN Guidelines for nmCRPC

• In addition to continuing ADT to maintain castrate serum levels of testosterone

(<50 ng/dL): ‒ For men whose PSADT is ≤10 months: apalutamide, darolutamide, enzalutamide, or other secondary hormone therapy ‒ For men whose PSADT is >10 months: observation or other secondary hormone therapy

NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020.

21

Case Conclusion

• Earl is taking apalutamide 240 mg/day and continuing ADT
• Bone health is being monitored closely
• Disease progression has plateaued

‒ PSA = 3.5 ng/mL

• Will continue serial PSA monitoring
• Will undergo imaging only if new symptoms develop or PSA level increases

22

• 72% increase from 2004 to 2013, even as incidence of low-risk prostate

cancer declined ‒ Trend started before USPSTF recommendation for reduced routine early screening so is not associated solely with that reduction

• 5-year survival rate: ~30% vs nearly 100% for nonmetastatic disease
• Approximately 90% of men with mCRPC have bone metastases
• Treatment evolving rapidly

‒ Novel therapies improve outcomes but increase treatment complexity

Metastatic Prostate Cancer

USPSTF = United States Preventive Services Task Force. American Cancer Society. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and- figures/2020/cancer-facts-and-figures-2020.pdf. Accessed Mar 24, 2020; NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020; Weiner AB, et al. Prostate Cancer Prostatic Dis. 2016;19:395-397; Vogelzang NJ et al. Clin Genitourin Cancer. 2017;15:42-52.

23

Case Study 2: Eli, 72 Years Old

• Eli has prehypertension and well-controlled diabetes

‒ Family history: mother had breast cancer

• Diagnosed 6 years ago with de novo metastatic prostate cancer, with a PSA level
• f 45 ng/mL
• Has high-volume disease: metastasis to multiple bone sites and to lymph nodes

24

Case Study (cont’d): Eli’s Initial Treatment

• Started on ADT and received 6 cycles of docetaxel

‒ His PSA level became undetectable but began to increase 2 years after he started treatment

• Presents with asymptomatic mCRPC

‒ Reports no pain ‒ Imaging unchanged since completion of chemotherapy

25

Sipuleucel-T

• First FDA-approved

immunotherapy for prostate cancer

• Shows OS benefit, even

without PSA response

• Most beneficial in less

advanced disease → thus, early use recommended

Treatment Options: Immunotherapy

Gupta S et al. Onco Targets Ther. 2011;4:79-96; Hu R et al. Ther Adv Urol. 2016;8:272-278; Kantoff PW et al. N Engl J Med. 2010;363:411-422.

Day 1

Leukapheresis

Days 2-3

Sipuleucel-T is manufactured

Days 3-4

Patient receives infusion

Apheresis Center Central Processing Clinician’s Office COMPLETE COURSE OF THERAPY Weeks 0, 2, 4

26

• AEs more frequent (≥20%) than

with placebo: chills, fatigue, pyrexia, nausea

• Explain to patients that

benefits may not manifest as typical signs of improvement (eg, changes in PSA)

Sipuleucel-T: Randomized Phase 3 IMPACT Trial

Kantoff PW et al. N Engl J Med. 2010;363:411-422; Pieczonka CM et al. Rev Urol. 2015;17:203-210.

Probability of Survival (%) 100 75 50 25 6 12 18 24 30 36 42 48 54 60 66

Sipuleucel-T: Survival Benefit in Phase 3 Trial

Placebo (n = 171) Median survival: 21.7 months Sipuleucel-T (n = 341) Median survival: 25.8 months P = .032 (Cox model) HR, 0.78 (95% CI, 0.61 – 0.98) Median survival benefit = 4.1 months Months Since Randomization

27

Case Study (cont’d)

• Eli undergoes 3 sessions of sipuleucel-T infusion over 4 weeks
• At interim assessment a few months later, his cancer has progressed, with

additional bone lesions revealed on scanning, but lymph node disease is stable

• He reports back pain that is not debilitating, but he now requires

intermittent opioids

28

• Both drugs are approved for use with or without prior docetaxel

Treatment Options for mCRPC: Newer ARSIs

CYP = cytochrome. Beer TM, et al. N Engl J Med. 2014;371:424-433; de Bono JS, et al. N Engl J Med. 2011;364:1995-2005; Gomez L, et al. Steroids. 2015;95:80-86; Ryan CJ, et al. N Engl J Med. 2013;368:138-148; Scher HI, et al. N Engl J Med; 2012;367:1187-1197.

Abiraterone

• Inhibits CYP17, enzyme needed

for androgen synthesis

• Administered with steroids

Enzalutamide

• Androgen receptor (AR)

antagonist; binds competitively to ligand-binding domain of AR

• Concomitant steroids not required

29

• Abiraterone vs placebo:

1195 patients with mCRPC progressing after docetaxel

• 2 prior chemo OS: 14.0 months

abiraterone vs 10.3 months placebo

• 1 prior chemo OS: 15.4 months

abiraterone vs 11.5 months placebo

• Most common AEs, grade ≥3:

‒ Fatigue (<9% vs 10%) ‒ Anemia (7% vs 8%) ‒ Back pain (<7% vs <10%)

COU-AA-301: Phase 3 Trial of Second-line Abiraterone in mCRPC

de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. HR, 0.65 (95% CI, 0.54-0.77) P <.001 Abiraterone Acetate Median survival: 14.8 months (95% Cl, 14.1-15.4) Placebo Median survival: 10.9 months (95% Cl, 10.2-12.0)

Months Survival (%)

100 80 60 40 20

0 3 6 9 12 15 18 21

30

6 12 18 24

Enzalutamide vs placebo for 1199 men with mCRPC after chemotherapy

Most common grade ≥3 AEs: fatigue (6% vs 7%), diarrhea (1% vs <1%), cardiac disorder (1% vs 2%)

AFFIRM: Phase 3 Trial of Second-line Enzalutamide in mCRPC

Scher HI, et al. N Engl J Med. 2012;367:1187-1197. 6 12 18 24 100 80 60 40 20

Months OS (%)

Enzalutamide Placebo HR, 0.63 (95% CI, 0.53-0.75) P <.001 100 80 60 40 20

Months rPFS (%)

Enzalutamide Placebo HR, 0.40 (95% CI, 0.35-0.47) P <.001

31

Phase 3 Trials in Chemotherapy-naïve mCRPC

Beer TM, et al. N Engl J Med. 2014;371:424-433; Ryan CJ, et al. Lancet Oncol. 2015;16:152-160; Ryan CJ, et al. N Engl J Med. 2013;368:138-148.

COU-302: Abiraterone + Prednisone PREVAIL: Enzalutamide

OS (Months) PFS (Months) OS (Months) PFS (Months) OS (%) PFS (%) OS (%) PFS (%)

Abiraterone + prednisone Placebo + prednisone

HR, 0.81 (95% CI, 0.70-0.93) P = .0033 HR, 0.53 (95% CI, 0.45-0.93) P = .0033

Abiraterone + prednisone Placebo + prednisone

HR, 0.71 (95% CI, 0.60-0.84) P <.001

Enzalutamide Placebo Enzalutamide Placebo

HR, 0.19 (95% CI, 0.15-0.23) P <.001

Men with mild or no symptoms Primary endpoints: OS, rPFS No prior ketoconazole Men with liver metastases eligible in PREVAIL

100 80 60 40 20 6 12 13 24 30 36 42 43 54 60 100 80 60 40 20 3 6 9 12 15 18 21 24 27 30 100 80 60 40 20 3 6 9 12 15 18 100 80 60 40 20 3 6 9 12 18 21 24 27 33 15 30

32

Abiraterone Enzalutamide

Dosage 1000 mg/day orally 160 mg/day orally Empty stomach required Yes No Prednisone required Yes No Drug interactions (CYP) Yes Yes Hypokalemia Yes No Lowers seizure threshold No Yes Potential liver toxicity Yes Less likely Hypertension Yes* Yes Fatigue Yes More likely Cardiac toxicity More likely Yes

Abiraterone and Enzalutamide: Drug Characteristics and Toxicities

*Risk of hypertension is increased by required coadministration of prednisone. Beer TM, et al. N Engl J Med. 2014;371:424-433; Mayo Clinic. www.mayoclinic.org/steroids/art-20045692. Accessed Mar 24, 2020; Moreira RB, et

• al. Oncotarget. 2017;8:84572-84578; Ryan CJ, et al. Lancet Oncol. 2015;16:152-160; Ryan CJ, et al. N Engl J Med. 2013;368:138-148; Tonyali S,

et al. Curr Urol. 2017;10:169-173; Zytiga [prescribing information]. Janssen Biotech; 2018.

33

0 3 6 9 12 15 18 21 24 27 30

• Unlike beta-emitting radioisotopes (eg, samarium-153), radium-223, an alpha-emitting isotope,

delivers less radiation to bone marrow, resulting in fewer effects of marrow suppression ALSYMPCA: randomized, placebo-controlled study of symptomatic mCRPC with bone metastases

Treatment Options: Radiopharmaceuticals ─Radium-223

Anderson M, Vogelzang N. pcri.org/insights-blog/2017/3/17/targeted-radiation-administered-by-injection. Accessed Mar 24, 2020; Parker C, et al. N Engl J Med. 2013;369:213-223; Parker C, et al. Prostate Cancer Prostatic Dis. 2018;21:37-47. Overall Survival Time to First Symptomatic Skeletal Event

HR, 0.70 (95% Cl, 0.58-0.83) P <.001 HR, 0.66 (95% Cl, 0.52-0.83) P <.001 Radium-223 (median OS, 14.9 months) Placebo (median time to first symptomatic skeletal event, 9.8 months) Placebo (median OS, 11.3 months) Radium-223 (median time to first symptomatic skeletal event, 15.6 months) Survival (%) Patients Without Symptomatic Skeletal Event (%) Months Since Randomization Months Since Randomization

100 80 60 40 20 0 3 6 9 12 15 18 21 24 27 30 33 36 39 100 80 60 40 20

Most common AEs: bone pain, nausea, anemia; no clinically meaningful between-group differences

34

Case Study (cont’d)

• Eli is treated with enzalutamide, which was chosen because of the extent of his

disease and to avoid steroids, which are necessary with abiraterone but are contraindicated for patients with diabetes

• Subsequently treated with radium-223
• After an initial decrease in PSA, his mCRPC progresses, with a PSA increase

to 38 ng/mL, and his use of opioids for pain has become more regular

35

Connors LM. Clin J Oncol Nurs. 2019;23:32-35; NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed Mar 24, 2020.

Role of Genetic Testing

• Germline mutations have raised the issue of inheritable cancer risk
• No validated biomarkers available; several are being investigated
• Every patient with prostate cancer should be considered for genetic testing

and possible genetic counseling

• Patients should be counseled before genetic testing

36

• PTEN loss may indicate increased risk of

disease progression

• AR-V7 leads to loss of binding in the AR

‒ May indicate resistance to ARSIs but not to taxanes

• DNA repair gene mutations

‒ Seen in approximately ¼ of patients with mCRPC ‒ Promising: BRCA1/BRCA2

Biomarkers: Examples of Potential Utility

AR-V7 = androgen receptor variant 7; PTEN = phosphatase and tensin homolog. Connors LM. Clin J Oncol Nurs. 2019;23:32-35; NCCN Guidelines. Prostate cancer. www.nccn.org/professionals/physician_gls/default.aspx. Accessed Mar 24, 2020.

Imaging Serum Tissue (biopsy) Urine

37

• Docetaxel (first-generation taxane)

‒ Until 2010, only approved drug to improve OS for mCRPC ‒ Appropriate for castrate-sensitive disease in select patients

• Cabazitaxel (next-generation taxane)

‒ Improves OS among docetaxel-pretreated patients with mCRPC ‒ Improves QoL; reduces pain through 10 treatment cycles ‒ Approved at lower dosage (20 mg/m2) in 2017 for patients with mCRPC previously treated with docetaxel ‒ Likely to move up in sequencing

Treatment Options: Chemotherapy

Bahl A, et al. BJU Int. 2015;116:880-887; de Wit R, et al. N Engl J Med. 2019;381:2506-2518; Eisenberger M, et al. J Clin Oncol. 2017;35:3198- 3206; Parimi S, et al. Int J Urol. 2016;23:726-733.

Cabazitaxel 2010 Docetaxel 2004 Cyclophosphamide 1993 5-FU 1991 Mitoxantrone 1996

38

CARD Trial: Randomized, Open-label Study of Cabazitaxel vs Abiraterone or Enzalutamide in mCRPC

de Wit R, et al. N Engl J Med. 2019;381:2506-2518.

rPFS OS Cabazitaxel ARSI

Months Patients With PFS (%)

100 90 80 70 60 50 40 30 20 10 3 6 9 12 18 24 30

Patients Who Were Alive (%)

100 90 80 70 60 50 40 30 20 10

Cabazitaxel

Months

3 6 9 12 18 24 30

ARSI

rPFS, months (95% CI) Cabazitaxel: 8.0 (5.7-9.2) ARSI: 3.7 (2.8-5.1) HR for progression or death, 0.54 (95% CI, 0.40-0.73) P = .001 Median OS, months (95% CI) Cabazitaxel: 13.6 (11.5-17.5) ARSI: 11.0 (9.2-12.9) HR for death, 0.64 (95% CI, 0.46-0.89) P = .008

N = 255 men with mCRPC that progressed ≤12 months on prior alternative ARSI (before or after docetaxel)

39

• Optimal sequencing not

established (sample shown)

• Treatment pathway is

unique for each patient

• Cross-resistance between

abiraterone and enzalutamide

• Need to identify molecular

subtypes for more rational sequencing

Example of Therapy Sequencing for mCRPC

*All treatment options should include ADT (surgical/medical orchiectomy). PARP = poly (ADP-ribose) polymerase. Li Y, et al. Am J Hematol Oncol. 2017;13:26-31; Lorente D, et al. Lancet Oncol. 2015;16:e279-92; Parente P, et al. Asia Pac J Clin Oncol. 2014;10:205-215; Sartor O. Clin Adv Hematol Oncol. 2015;13:570-572; Sartor O, et al. N Engl J Med. 2018;378:645-657; Terada N, et al. Int J Urol. 2017;24:441-448.

First Line* Sipuleucel-T (chemonaïve) Abiraterone

• r

Enzalutamide

• r

Docetaxel Abiraterone

• r

Enzalutamide Docetaxel

• r

Cabazitaxel Docetaxel

• r

Radium-223 (bone metastases) Cabazitaxel

• r

Radium-223 (bone metastases) Clinical Trials (eg, PARP inhibitors, immunotherapy) Second Line* Third Line* Treatment Exhaustion Asymptomatic Symptomatic mCRPC Patient

40

Several Novel Agents Are Under Study

MSI-H = microsatellite instability-high. ASCO Post Staff. ascopost.com/news/february-2020/talazoparib-for-pretreated-patients-with-metastatic-castration-resistant-prostate-cancer/. Accessed March 24, 2020; Boettcher AN et al. Front Oncol. 2019;9:884; Clarke N, et al. Lancet. 2018;19:975-986; Hansen AR, et al. Ann Oncol. 2018;29:1807- 1813; Hussain M, et al. ESMO 2019 Congress. Abstract LBA12_PR; Smith MR, et al. Ann Oncol. 2019;30(suppl 5):v884-v885; Zhu J. www.urotoday.com/conference-highlights/asco-2018/asco-2018-prostate-cancer/104947-asco-2018-keynote-199-pembrolizumab-for-docetaxel- refractory-metastatic-castration-resistant-prostate-cancer-mcrpc.html. Accessed Mar 24, 2020. Clinicaltrials.gov. NCT02975934. Accessed April 9, 2020.

Olaparib: Phase 3 study in mCRPC with homologous recombination repair (HRR) mutation granted FDA priority review Niraparib: Phase 2 study for BRCA1/BRCA2 gene-mutated mCRPC → breakthrough therapy designation

Pembrolizumab: Tissue-agnostic approval (for MSI-H) Has shown promise in prostate cancer studies Ipilimumab: Being studied in phase 1, 2, and 3 trials in prostate cancer

IMMUNE CHECKPOINT INHIBITORS PARP INHIBITORS

Talazoparib: Promising interim results from phase 2 TALAPRO-1 study Rucaparib: Priority review for supplemental NDA granted from FDA based on phase 3 TRITON3 trial

41

PROfound Trial: Phase 3 Study of Olaparib vs Enzalutamide or Abiraterone for mCRPC With HRR Gene Alterations

ATM = ataxia-telangiectasia mutated gene product; BICR = blinded independent central radiology; NHA = new hormonal agent; ORR = objective response rate; TTPP = time to PSA progression. Hussain M, et al. ESMO 2019 Congress. Abstract LBA12_PR.

Key Eligibility Criteria mCRPC with disease progression on prior NHA, eg, abiraterone

• r enzalutamide

Alterations in ≥1 of any qualifying gene with a direct or indirect role in HRR

2:1 Randomization Open Label

Cohort A: BRCA1, BRCA2, or ATM N = 245 Cohort B: Other alterations N = 142

Upon BICR progression, physician’s choice patients were allowed to cross over to olaparib

Physician’s Choice n = 83 Olaparib 300 mg bid n = 162 Physician’s Choice n = 48 Olaparib 300 mg bid n = 94 Endpoints Primary:

• rPFS in Cohort A

Secondary:

• rPFS in Cohorts

A & B

• ORR in Cohort A
• TTPP in

Cohort A

• OS in Cohort A

42

• Patients with mCRPC + HRR

alterations who progressed on prior abiraterone + prednisone and/or enzalutamide had significantly improved rPFS and ORR vs physician’s choice of either enzalutamide or abiraterone + prednisone

• Favorable trend for OS was
• bserved despite crossover by a

large proportion of patients initially treated with physician’s choice hormonal therapy

PROfound Trial: Results

Hussain M, et al. ESMO 2019 Congress. Abstract LBA12_PR.

Cohort A: rPFS by BICR Among Patients With Alterations in BRCA1, BRCA2, or ATM

Probability of rPFS Time From Randomization (months)

Prespecified sensitivity analysis based on investigator assessment: HR, 0.24% (95% Cl, 0.17-0.34); P <.0001

0 1 1.0 0.8 0.6 0.4 0.2 0.0 3 5 7 9 11 13 15 17 19 21

6-month rate 59.76% 22.63 12-month rate 28.11% 9.40% Olaparib Physician’s choice Events (%) Median PFS (months) HR (95% Cl) 106 (65.4) 7.39 68 (81.9) 3.55 0.34 (0.25-0.47) P <.0001

43

Oral PARP inhibitor for BRCA 1/2 gene-mutated mCRPC (prior taxane chemo and AR-targeted therapy)

Phase 2 GALAHAD Study: Breakthrough Therapy Designation for Niraparib for Treatment of mCRPC

Smith M, et al. oncologypro.esmo.org/Meeting-Resources/ESMO-2019-Congress/Pre-specified-interim-analysis-of-GALAHAD-A-phase-2-study-of- niraparib-in-patients-pts-with-metastatic-castration-resistant-prostate-cancer-mCRPC-and-biallelic-DNA-repair-gene-defects-DRD. Accessed Mar 24, 2020.

Response BRCA1/2 (n = 46) n (%) (95% CI) Non-BRCA (n = 35) n (%) (95% CI)

ORR 12/29 (41) (23.5-61.1) 2/22 (9) (1.1-29.2) ≥50% Decline in PSA 23/46 (50) (34.9-65.1) 1/35 (3) (0.1-14.9) Circulating Tumor Cells Conversion 18/38 (47) (31.0-64.2) 5/24 (21) (7.1-42.2) Composite Response Rate 29/46 (63) (47.6-76.8) 6/35 (17) (6.6-33.7)

Months (95% CI) Months (95% CI)

Median rPFS, months (95% CI) 8.2 (5.2-11.1) 5.3 (1.9-5.7) Median OS, months (95% CI) 12.6 (9.2-15.7) 14.0 (5.3-20.1)

44

Case Conclusion

• Eli receives 20 mg/m2 of cabazitaxel every 3 weeks
• His blood pressure and neutrophil count are monitored regularly
• At the end of first treatment cycle:

‒ PSA has decreased to 7 ng/mL ‒ He reports decreased pain ‒ Bone scans show stable lesions and no new lesions ‒ Blood pressure has not increased

45

• Patient and clinician perceptions of AEs may

differ: Communication is key

• Monitor and manage AEs to optimize

adherence and treatment benefit

• High costs of some treatments may make

them unattainable for some patients and/or affect adherence ‒ Investigate financial assistance programs

Overcoming Barriers to Effective Treatment

Bultijnck R, et al. Eur Urol Focus. 2016;2:514-521; Buonerba C, et al. J Cancer. 2017;8:2663-2668; Pollard ME, et al. Asian J Urol. 2017;4:37-43; Sartor O, et al. N Engl J Med. 2018;378:645-657.

46

• Skeletal: resistance exercise; bone-protective agents
• Metabolic: exercise (aerobic and resistance); diet;

treatment for dyslipidemia, hypertension; monitoring/treatment for diabetes

• Fatigue: exercise (aerobic and resistance)
• Hot flushes: medroxyprogesterone, venlafaxine,

gabapentin

• Gynecomastia: prophylactic radiation, tamoxifen

Evidence-based Strategies to Reduce AEs of ADT and Other Treatments

Bultijnck R, et al. Eur Urol Focus. 2016;2:514-521; Buonerba C, et al. J Cancer. 2017;8:2663-2668; Pollard ME, et al. Asian J Urol. 2017;4:37-43; Sartor O, et al. N Engl J Med. 2018;378:645-657.

47

PCE Action Plan

✓ For patients with mHSPC, consider adding docetaxel (± prednisone), abiraterone + steroid, apalutamide, or enzalutamide to ADT ✓ Implement shared decision-making to optimize treatment outcomes ✓ Consider early use of approved agents for nmCRPC to improve MFS ✓ Consider genetic testing and possible genetic counseling for all patients with prostate cancer PCE Promotes Practice Change

2020 Spring Oncology Conference