Joelle Hamilton, M.D.

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1 Joelle Hamilton, M.D.

3 Case Presentation: CRPC, Rising PSA 70 yo healthy, fit, active man post RALP 8 years prior with rising PSA Rising PSA from 0.02 nadir to 3.4 thus ADT intitiated per Urologist On ADT, rising PSA from 0.8 nadir to 4.6, T <50 Castrate Resistant Prostate Cancer: M0 vs M1? Bone scan and CT A/P negative for mets Current standard of care per NCCN Guidelines ADT alone and continue to follow ADT and participation in a clinical trial ADT and hormonal manipulation PET Axumin to evaluate for M1 disease not seen on conventional imaging

5 Multisite experience of fluciclovine ( 18 F) PET/CT imaging in biochemically recurrent prostate cancer: Impact of clinical factors and intersite variation PSA (ng/ml)] DR (%) Subject (n = 542) Prostate/bed (n = 549) Extraprostatic (n = 537) < > > > > > Zanoni et al, GU ASCO 2017 Abstract 163

6 Comparison of Imaging for Rising PSA post Treatment DM Schuster, et al. J Urol 2014;191(5):

7 PET Axumin vs CT Positivity by PSA Range DM Schuster et al, J of Uro 2014

8 Case Presentation Rising PSA - CRPC PET Axumin reveals L2 VB met, right iliac met, retroperitoneal lymph nodes ADT continued, oral agent initiated for treatment, Provenge Response assessed by declining PSA what imaging as PET Axumin is not yet approved for follow up evaluation studies ongoing

11 Case Presentation Hormone Naïve Metastatic Disease 63 yr old attorney, initial PSA 7.1 at diagnosis with biopsy of prostate revealing Gleason 4+3 prostate cancer in 7/12 biopsy specimens Robot-assisted Laparoscopic Prostatectomy with path revealing bilateral 4+3 prostate cancer, extraprostatic extension, perineural invasion, negative margins Adjuvant radiation discussed with patient Erectile dysfunction evaluated, treated

12 Case Presentation continued PSA post-op 0.4 then post RT increased from 2 range up to 12 Restaging based upon the RADAR I criteria Image when PSA rises to 2, 5, 10, and doubling thereafter Prostate Cancer, post treatment with rising PSA Staging to evaluate rising PSA post prostatectomy/radiation CT with mediastinal, supraclavicular, retroperitoneal LN enlargement and T10 vertebral body mets Bone scan with T10 and left hip increased uptake Normal CBC, CMP; PSA 18

13 Hormone Naïve Prostate Cancer

14 ADT + docetaxel: a new standard of care for men with mcnpc and high metastatic burden (2015) Presented By Karim Fizazi at 2017 ASCO Annual Meeting

15 Metastatic disease: Stampede Presented By James Catto at 2017 Genitourinary Cancers Symposium

16 CHAARTED chemohormonal therapy in M1 HSPC MS 57.6 v 44 months High Volume Disease 49.2 v 32.2 months Low Volume Disease NR v NR Scher, NEJM 2012 Sweeney CJ et al. N Engl J Med 2015;373:

17 CHAARTED HRs in Chemohormonal Therapy

18 Metastatic disease: Docetaxol Presented By James Catto at 2017 Genitourinary Cancers Symposium

19 Metastatic disease: Docetaxol Presented By James Catto at 2017 Genitourinary Cancers Symposium

20 ADT, Docetaxel 6 cycles Pt continued to work, travel, exercise PSA declined to 0.02 with castrate T ADT continued Bone Health Vitamin D and Calcium daily, weight bearing exercise No benefit to addition of ZA to chemohormonal therapy in HSPC M1 disease Clinical update PSA 0.01, scans show resolved adenopathy, sclerosis of bone metastasis

21 What Makes an Oncologist Giddy? Paper charts! Thriving patient enjoying and living their life!! Strong Wifi in the office! Survival data from ASCO!

22 Abiraterone mechanism of action: <br />androgen biosynthesis inhibitor Presented By Karim Fizazi at 2017 ASCO Annual Meeting

23 Slide 1 Presented By Nicholas James at 2017 ASCO Annual Meeting

24 Slide 30 Presented By Nicholas James at 2017 ASCO Annual Meeting

25 Slide 53 Presented By Nicholas James at 2017 ASCO Annual Meeting

26 Slide 56 Presented By Nicholas James at 2017 ASCO Annual Meeting

27 Slide 63 Presented By Nicholas James at 2017 ASCO Annual Meeting

28 Slide 71 Presented By Nicholas James at 2017 ASCO Annual Meeting

29 Presented By Nicholas James at 2017 ASCO Annual Meeting

30 Practice Changing? Presented By Charles Ryan at 2017 ASCO Annual Meeting

31 LATITUDE: A phase 3, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos <br />in newly diagnosed high-risk metastatic hormone-naïve prostate cancer patients Presented By Karim Fizazi at 2017 ASCO Annual Meeting

32 Objective Presented By Karim Fizazi at 2017 ASCO Annual Meeting

33 Statistically significant 38% risk reduction of death Presented By Karim Fizazi at 2017 ASCO Annual Meeting

34 Statistically significant 53% risk reduction of radiographic progression or death Presented By Karim Fizazi at 2017 ASCO Annual Meeting

35 Adverse events of special interest Presented By Karim Fizazi at 2017 ASCO Annual Meeting

36 Slide 24 Presented By Karim Fizazi at 2017 ASCO Annual Meeting

38 Case CRPC with Bone and LN Mets 70 yr old, Gleason 4+3 disease post localized RT 5 years previously PSA increase thus ADT for 1 year in the setting of HSPC M0 disease PSA increased to 14 thus restaging with bone scan showing bone mets pelvis and L spine, CT A/P showing LN mets (pelvis, RP) with obstruction Type 2 Diabetes newly diagnosed on initial evaluation labs Very active professional, married, no tobacco, rare alcohol, family history of lung cancer (smoker) Castrate resistance confirmed with T 20 Minimal symptoms rare pain requiring Tylenol Treatment options?

39 NCCN Guidelines for CRPC

42 Treatment Options for Metastatic CRPC

43 George D. Urology. 2013; 82; Slide source Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26: [10] Kantoff PW, Higano CS, Shore ND, et al; the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363: [11] de Bono JS, Oudard S, Ozguroglu M, et al; TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376: [12] de Bono JS, Logothetis CJ, Molina A, et al; COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364: [13] Scher HI, Fizazi K, Saad F, et al; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367: [14] Parker C, Heinrich D, O'Sullivan JM, et al. Overall survival benefit and safety profile of radium- 223 chloride, a first-in-class alpha- pharmaceutical: results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. J Clin Oncol. 2012;30(Suppl 5) Abstr 8.

44 Sipuleucil-T (Provenge)

45 Sip-T/Provenge Survival Data Kantoff PW, Higano CS, Shore ND, et al; the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:

46 Who should be treated with Sip-T/Provenge? Metastatic castrate resistant prostate cancer, no visceral mets Asymptomatic or minimally symptomatic No narcotics More than 6 months life expectancy Generally no long term steroids greater than replacement dose Before numerous hormonal agents, prior to chemotherapy although can be used if controlled disease after chemotherapy

47 Beer et al. NEJM 2014 Enzalutamide prior to Chemotherapy rpfs, Survival Data

48 Ryan, et al. NEJM 2013 Abiraterone/Prednisone prior to Chemotherapy rpfs and Survival

49 Parker, et al. NEJM 2013 Radium-223 Survival and SSE Data

50 Radium-223/Xofigo Patient Selection Castrate resistant prostate cancer Two or more bone mets on bone scan No visceral mets Lymph nodes <= 3cm Symptoms due to prostate cancer - analgesics or radiation for pain Adequate performance status (ECOG 0-2)

51 Cabazitaxel after Docetaxel Survival Option for patients who have been treated with AA or Enza and Docetaxel debono, et al. Lancet 2010

52 Restaging, Progression, Choice of Treatment Options- RADAR II Limited nonrandomized head-to-head comparison trials of options Safety and tolerability, co-morbid conditions Risks and benefits of potentially combining options overlapping toxicities, different mechanism of action Logistics regarding access to care Reimbursement Therapeutic layering a clinical point where one or more agent(s) are added onto existing therapy RADAR II Radiographic Assessment for Detection of Advanced Recurrence II (Crawford, et al. Urology 2017)

53 Determining Progression Convincing, consistent rise in PSA Radiographic progression Clinical symptoms Sipuleucel-T best used with lower tumor burden present, PSA <22 Improvement in PSA/imaging should not be expected Androgen Inhibitors low and high burden disease AR splice variant in CTCs as potential biomarkers Radiographic and symptom progression Bone scan flare, PSA/AlkPhos may rise initially w Abiraterone (0-3 months) PSA rising to trigger reevaluation Radium-223 when bone mets and symptoms, when progress on Abi/Enza PSA change does not correlate with survival benefit; AlkPhos can be a marker Can layer with Abi/Enza Chemotherapy if rapid visceral progression, rapid progression on oral agents PSA may rise prior to falling Stopping point is radiographic or clinical progression

54 RTOG 0521 Docetaxel in the High Risk Adjuvant Setting Radiation + ADT for 2 years +/- Docetaxel 75 mg/m2 q 21 days, 6 cycles Docetaxel initiated 4 weeks after the completion of RT Eligible patients Gleason 8-10 PSA >= 20 >= T2 disease Patient Population Median PSA 15 53% Gleason % N1 4-year Survival 89% v 93% (p 0.04) 6-year DFS 55% v 65% (p 0.04) Not yet published in a peer-reviewed setting Sandler et al. LBA5002, ASCO 2015

55 A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study of Continued Enzalutamide Post Prostate-Specific Antigen Progression in Men With Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer Presented By Charles Ryan at 2017 ASCO Annual Meeting

56 PLATO: Novel Trial Design Presented By Charles Ryan at 2017 ASCO Annual Meeting

57 Primary Endpoint: PFS Presented By Charles Ryan at 2017 ASCO Annual Meeting

58 Conclusions Presented By Charles Ryan at 2017 ASCO Annual Meeting

59 THANK YOU Joelle Hamilton, M.D.

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia

SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract on Prostate Cancer) In Oncologia Divisione di Oncologia Medica Unità Tumori Genitourinari SESSIONE PLATINUM SERIES (Best Papers Poster o Abstract