NCCN Prostate Cancer Guidelines Update. James L. Mohler, MD Roswell Park Cancer Institute

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1 NCCN Prostate Cancer Guidelines Update James L. Mohler, MD Roswell Park Cancer Institute

2 Every 2.5 Minutes an American is Diagnosed with Prostate Cancer Every 15 Minutes an American Dies of Prostate Cancer

3 Major Updates 1. Active surveillance monitoring made more rigorous 2. Immunotherapy for asymptomatic or minimally symptomatic castrationrecurrent metastatic prostate cancer 3. Cabazitaxel for docetaxel failure 4. Denosumab to prevent skeletal-related events

4 U.S. Annual Age- Adjusted Incidence Rates Cancer Statistics, 2010

5 U.S. Annual Age-Adjusted Mortality Rates, Cancer Statistics, 2010

6 PSA and Prostate Cancer 1980s: 16% diagnosed with metastatic CaP 2002: 4% diagnosed with metastatic CaP CaP mortality rate declined 33% from 1993 to 2003 Tyrol PSA-based screening study (Bartsch G, BJU Int, 2008) shows 54% decline in CaPspecific mortality and 10 yr PSA lead-time

7 CaP Screening Recommendations American Urological Association (August 2009) Annual PSA & DRE - From age 50 until LE <10 yrs - From age 40 if high risk (AA or family history) American Cancer Society (March 2010) - Annual PSA ± DRE - From age 50 until LE <10 yrs - From age 45 if high risk (AA or family history) - From age 40 if multiple family members

8 CaP Screening Recommendations American College of Physicians; American Academy of Family Physicians Counsel men 50 to 65 regarding risk vs. benefit U.S. Preventive Services Task Force (August 2008) Routine screening not advocated especially >75 NCCN (the best recommendation) (August 2009) PSA and DRE at 40 (category 2B), if <1, at 45 PSA and DRE at 45, if <1, at 50 If high risk because African American, family history or PSA >1, annual PSA and DRE at 40 (category 2B) Routine screening less frequent in older men (65-75) and not advocated especially >75

9 Use of PSA for Early Detection is Most Appropriate for: A) African Americans B) Men with CaP in father or brother C) Men with life expectancy 10 yrs D) Men with BRAC1 mutation E) All of the above

10 March 26, 2009 CaP Explosion NEJM 360: and

11 Need to Treat to Prevent 1 Death: 48 screen-detected CaP (European Study) No survival benefit (American Study) 100 low risk CaP (Klotz, J Clin Oncol, 2005)

12 Goteburg Study Subset of European study (ERSPC) Population-based 1:1 randomization of 20,000 men PSA q 2 yrs Age yrs Evaluation for PSA >3.0 (>2.5 since 2005) Follow-up 14 yrs (ERSPC 9, PLCO 11.5) CaP diagnosis 12.7% screened group 8.2% control group Hugosson, Lancet Oncol, 2010

13 CaP mortality Goteburg Study 0.5% screened group 0.9% control group 40% absolute cumulative-risk reduction of CaP death (European~15%, American 0) To prevent a CaP death: Screen 293 men (European 1410) Treat 12 men (European 48) Hugosson, Lancet Oncol, 2010

14 NCCN Concerns High prevalence of CaP upon autopsy Sakr, In Vivo, 1994 High frequency of CaP upon biopsy even when PSA and DRE normal Thompson, NEJM, 2004 Mortality about 1/6 incidence Jemal, CA Cancer J Clin, % of screen-detected CaP overtreated Etzioni, JNCI, 2002; Draisma, JNCI, 2003; Miller, JNCI, 2006

15 Active Surveillance or Immediate Active Treatment? The risks of AS include chance of missed opportunity for cure nerve-sparing may be more difficult anxiety The benefits of AS include avoidance of treatment-related side effects from a treatment that was unnecessary

16 2010 Guideline Updates 1. Very low risk CaP Low Risk T1-T2a GS 2-6 PSA<10 Very Low Risk T1c GS 2-6 PSA<10 <3 cores positive <50% CaP in any core PSAD<0.15

17 2010 Guideline Updates 2. Active surveillance only recommendation for men with: a. Low risk CaP and L Exp < 10 yrs b. Very low risk CaP and L Exp < 20 yrs

18 2011 Guideline Updates 3. Active surveillance program clarified a. PSA as often as every 3 mo but at least every 6 mo b. DRE as often as every 6 mo but at least every 12 mo c. Needle biopsy may be repeated within 6 mo of diagnosis if initial bx was < 10 cores; may be performed within 18 mo of initial biopsy >/= 10 cores d. Uncertain what the progression criteria should be to warrant treatment

19 2011 Guideline Updates 3. Active surveillance program clarified a. PSA as often as every 3 mo but at least every 6 mo b. DRE as often as every 6 mo but at least every 12 mo c. Needle biopsy may be repeated within 6 mo of diagnosis if initial bx was < 10 cores; may be performed within 18 mo of initial biopsy >/= 10 cores d. Uncertain what the progression criteria should be to warrant treatment

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23 North American AS Experience Center Toronto 1 Johns Hopkins 2 UCSF 3 No. Patients Age (yr) F/U (mo) OS 68% 98% 98% CSS 97% 100% 100% Treatment 30% 25% 24% GS 8% 19% 38% 16% PSA 14% (DT<3 yrs) - 26% (PSAV>0.75) Nodule 1% - - Anxiety 3% 7% 8% 1. Klotz, J Clin Oncol, 2010; 2. Carter, J Urol, 2007; Sheridan, J Urol, 2008; 3. Dall Era, Cancer, 2008

24 Progression on Active Surveillance Institution Median F/U Criteria Rate Toronto 8 yrs PBx, PSADT 23% Johns Hopkins 4 yrs PBx 19% UCSF 4 yrs PBx, PSAV 16%

25 Optimal Criteria for Progression: Toronto Experience 305 (of 450) Canadians followed median 6.8 yrs without progression clinically or by PSADT<3 yrs % who meet PSA trigger for treatment PSA threshold 10 or PSADT calculated various ways PSAV > 2ng/ml/yr Conclusion: Can t improve on PSADT<3 yrs Loblaw, J Urol, 2010

26 Optimal Criteria for Progression: Johns Hopkins Experience 290 men with NCCN low risk CaP Semiannual PSA and DRE Annual prostate biopsy Progression by prostate biopsy criteria only 102 (35%) progression at median F/U 2.9 yrs Neither PSADT (AUC 0.59) or PSAV (AUC 0.61) was associated with prostate biopsy progression Conclusion: PSA kinetics cannot replace annual prostate biopsy Ross, JCO, 2010

27 Optimal Criteria for AS: UCSF Experience Risk of 4 yr disease progression Gleason Score Low risk 35% Intermediate risk 30% PSADT < 3yrs Low risk 11% Intermediate risk 10% Conclusion: Risk of progression at 4 yrs similar for low and intermediate risk Cooperberg, JCO, 2010

28 Harm by AS: UCSF Experience Surgical Pathology Median months of follow-up after start of AS or primary RP AS+RP (n=74) RP (n=148) IQR Gleason Grade (3+4) (4+3) Pathologic T stage, T Pathologic N stage, N Positive margins, yes Extracapsular extension, yes Seminal vesicle invasion, yes BPFS 100% 97% Cooperberg, JCO, 2010 P

29 Harm by AS: Toronto Experience 450 men followed median 6.8 yrs Survival: Overall 78.6% CaP-specific 92.2% Progression: 30% (n=145) 8% Gleason score 14% PSADT<3 yrs 1% Nodule 3% Anxiety Treatment (n=135) Radical prostatectomy 35 XRT ± ADT 90 ADT 10 Follow-up available (n=11) 5 yr BPFS 47% RP 62% XRT 43% Conclusion: Curative treatment may not be possible for men who progress on AS Klotz, JCO, 2010

30 Active Surveillance Conundrums Overtreatment rates estimated at up to 50% Criteria for AS and progression differ in the large clinical series Treatment of all who meet any progression criteria prevents evaluation of that criteria PSA kinetics appear to over detect progression and may not detect progression when prostate cancer remains curable Prostate biopsies not without risk Urosepsis rates increasing Nerve preservation may become problematic

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34 Sipuleucil-T: Mechanism of Action Antigen (PAP- GMCSF) is exposed to an Antigen Presenting Cell (APC) APC takes up the antigen Antigen is processed and presented on surface of the APC Fully activated, the APC is now sipuleucel-t and is collected INFUSE PATIENT T-cells proliferate and attack cancer cells sipuleucel-t activates T- cells in the body Courtesy of Philip Kantoff

35 Sipuleucel-T: Logistics of Therapy Day 1 Leukapheresis Day 2-3 Sipuleucel-T is manufactured Day 3-4 Patient is infused Apheresis Center Central Processing Doctor s Office COMPLETE COURSE OF THERAPY: Weeks 0, 2, 4 Courtesy of Philip Kantoff

36 Randomized Phase III Trial of Sip-T in CRPC (D9901) Asymptomatic metastatic CRPC (N=127) Placebo q2wks x 3 (N=45) Sip-T q2wks x 3 (N=82) P R O G R E S S I O N APC8015F q2wks x 3 Long-term follow-up Small, JCO, 2006

37 Percent Without Progression Results: Time to Objective Progression APC8015 (n=82) Placebo (n=45) P=0.061 (log-rank) HR=1.43 (95% CI: 0.98, 2.09) Time to Objective Disease Progression (weeks) Small, JCO, 2006

38 Percent Survival Results: Overall Survival APC8015 (N=82) Placebo (N=45) P=0.01 (log-rank) HR=1.7 (95% CI: 1.126, 2.563) Survival (months) Small, JCO, 2006

39 Randomized Phase 3 IMPACT Trial (Immunotherapy Prostate AdenoCarcinoma Treatment) Asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (N = 512) 2:1 Sipuleucel-T Q 2 weeks x 3 Placebo Q 2 weeks x 3 Primary endpoint: Overall survival Secondary endpoint: Objective disease progression P R O G R E S S I O N Treated at physician discretion Treated at physician discretion and/or salvage protocol S U R V I V A L Kantoff, NEJM, 2010

40 IMPACT Overall Survival Final Analysis (349 events) 36.5 mo median f/u HR = (95% CI, 0.606, 0.951) P = (Cox model) Median survival benefit = 4.1 months Sipuleucel-T (n = 341) Median survival: 25.8 mo. 36 mo. survival: 32.1% Placebo (n = 171) Median survival: 21.7 mo. 36 mo. survival: 23.0% No. at Risk Sipuleucel-T Placebo Kantoff, NEJM, 2010

41 Sipuleucel-T PSA responses are few (2%) No clinical changes occur After sipuleucel-t, treat patient as clinically indicated Limited availability during first year NJ expansion; LA opened; Atlanta soon American Red Cross for plasmaphoresis

42 Sipuleucel-T FDA approved April 2010 CMS National Coverage Determination June 2011 Patient Assistance Program FDA-CMS differences FDA based on registration trial eligibility Visceral metastases, survival > 6 mo, PF 0-1 Dendreon issues earnings guidance Aug 2011 Stock falls >70% in 20 minutes

43 Unresolved Issues What is appropriate timing? Before or after secondary androgen deprivation therapy After chemotherapy? How long after? After steroids? For how long should steroids be stopped? Predicting who will benefit? Biomarkers of benefit from treatment

44 Which is true about Sipuleucel-T? 1. Indicated for patients with asymptomatic or minimally symptomatic metastatic castration-recurrent CaP 2. Prolongs time to disease progression 3. Should be given with low dose steroids 4. Uses PSA as the target antigen

45 Which is true about Sipuleucel-T? 1. Indicated for patients with asymptomatic or minimally symptomatic metastatic castration-recurrent CaP 2. Prolongs time to disease progression 3. Should be given with low dose steroids 4. Uses PSA as the target antigen

47 Phase III Trials of Docetaxel Docetaxel/Pred vs Docetaxel Combined With: Combinations Status Results DN-101 Terminated early Negative GVAX Terminated early Negative Bevacizumab Completed Negative VEGF-Trap Maturing Pending Atrasentan Maturing Pending ZD4054 Maturing Pending Dasatinib On-going Pending Lenalidomide On-going Pending Custersin (OGX-011) On-going Pending No combination improves on docetaxel

48 Cabazitaxel New semi-synthetic taxane Selected to overcome the emergence of taxane resistance Preclinical data As potent as docetaxel against sensitive cell lines and tumor models Activity against tumor cells and tumor models that are resistant to docetaxel Clinical data DLT was neutropenia in Phase I trials Antitumor activity in mcrpc in Phase I trials including docetaxel-resistant disease

49 TROPIC: Phase III Study mcrpc patients who progressed during and after treatment with a docetaxel-based regimen (N = 755) Stratification factors ECOG PS (0, 1 vs. 2) Measurable vs. non-measurable disease Cabazitaxel 25 mg/m² q 3 wk + prednisone for 10 cycles (n = 378) Mitoxantrone 12 mg/m² q 3 wk + prednisone for 10 cycles (n = 377) Primary endpoint: OS Secondary endpoints: Progression-free survival (PFS), response rate, and safety Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression DeBono, Lancet, 2010

50 Proportion of OS (%) Primary Endpoint: Overall Survival (ITT Analysis) Median OS (months) Hazard Ratio 95% CI P-value MP CBZP < months 6 months 12 months 18 months 24 months 30 months Number at risk MP CBZ DeBono,Lancet, 2010

51 Cabazitaxel Cabazitaxel Conclusions 30% risk reduction of death (HR = 0.70, P < ) Median OS improvement in favor of CBZP: 15.1 months vs 12.7 months OS benefit was consistent across subgroups Secondary endpoints (PFS, RR, and TTP) also improved significantly Consider growth factor support for significant granulocytopenia DeBono, Lancet, 2010

53 Prevention of skeletal-related events (SREs) in patients with metastatic CRPC Zoledronic acid reduces SREs by 20% Zoledronic acid (Z) versus denosumab (D) 1,901 patients with mcrpc Patients randomized to D (120 mg SC q 4 weeks) or Z (4 mg IV q 4 weeks). D delayed the time to the first on-study SRE (a fracture, need for bone radiation, need for bone surgery, or spinal cord compression) compared with Z (hazard ratio = 0.82) D reduced the rate of multiple SREs compared to Z (HR = 0.82) Rate for osteonecrosis of the jaw similar: 22 men treated with D and in 12 men treated with Z OS and TTP were similar Fizazi, JCO, 2010

54 Which is not true? 1. Cabazitaxel prolongs survival in men with castration-recurrent CaP who have progressed on docetaxel 2. Denosumab prolongs survival over placebo or zoledronic acid 3. Cabazitaxel's dose-limiting toxicity is neutropenia 4. Denosumab may cause osteonecrosis of the jaw

55 Which is not true? 1. Cabazitaxel prolongs survival in men with castration-recurrent CaP who have progressed on docetaxel 2. Denosumab prolongs survival over placebo or zoledronic acid 3. Cabazitaxel's dose-limiting toxicity is neutropenia 4. Denosumab may cause osteonecrosis of the jaw

56 Case 1 A common presentation of clinically localized CaP Change patient s health and use NCCN guidelines to estimate life expectancy Examine effect upon relationship between risk of death from CaP vs other causes Use NCCN guidelines to see how recommended treatment changes

57 Case 65 yo man presents with PSA 7.2, clinical stage T1c, and Gleason score 3+3=6 prostate cancer in 10% of 1 of 12 biopsies. Health is excellent. The best choice for treatment is: 1. 3D Conformal Radiation 2. Interstitial Implant (seeds) 3. Prostatectomy 4. Cryotherapy 5. Active Surveillance

58 CaP-limited LExp is 12 (low aggressiveness) + 3 (ADT) + 10 (PSA lead time) = 25 yrs LExp by age = 16.4 yrs - Excellent health = 24.6 yrs - Average health = 16.4 yrs - Poor health = 8.2 yrs Chance of CaP death - Excellent health = 50% - Average health = 10% - Poor health = 0% Chance of cure of CaP by Partin Tables 83% Chance of CaP death after RP - Excellent health = 7% - Average health = 2% - Poor health = 0%

59 Case 65 yo man presents with PSA 7.2, clinical stage T1c, and Gleason score 3+3=6 prostate cancer in 10% of 1 of 12 biopsies. Health is excellent. The best choice for treatment is: 1. 3D Conformal Radiation 2. Interstitial Implant (seeds) 3. Prostatectomy 4. Cryotherapy 5. Active Surveillance

60 Case 65 yo man presents with PSA 7.2, clinical stage T1c, and Gleason score 3+3=6 prostate cancer in 10% of 1 of 12 biopsies. Health is poor. The best choice for treatment is: 1. 3D Conformal Radiation 2. Interstitial Implant (seeds) 3. Prostatectomy 4. Cryotherapy 5. Active Surveillance

62 Case 65 yo man presents with PSA 7.2, clinical stage T1c, and Gleason score 3+3=6 prostate cancer in 10% of 1 of 12 biopsies. Health is poor. The best choice for treatment is: 1. 3D Conformal Radiation 2. Interstitial Implant (seeds) 3. Prostatectomy 4. Cryotherapy 5. Active Surveillance

63 Case 65 yo man presents with PSA 7.2, clinical stage T1c, and Gleason score 3+3=6 prostate cancer in 10% of 1 of 12 biopsies. Health is average. The best choice for treatment is: 1. 3D Conformal Radiation 2. Interstitial Implant (seeds) 3. Prostatectomy 4. Cryotherapy 5. Active Surveillance

65 Case 65 yo man presents with PSA 7.2, clinical stage T1c, and Gleason score 3+3=6 prostate cancer in 10% of 1 of 12 biopsies. Health is average. The best choice for treatment prior to 2010 was: 1. 3D Conformal Radiation 2. Interstitial Implant (seeds) 3. Prostatectomy 4. Cryotherapy 5. Active Surveillance

66 Case 65 yo man presents with PSA 7.2, clinical stage T1c, and Gleason score 3+3=6 prostate cancer in 10% of 1 of 12 biopsies. Health is average. The only treatment recommendation beginning 2010 is: 1. 3D Conformal Radiation 2. Interstitial Implant (seeds) 3. Prostatectomy 4. Cryotherapy 5. Active Surveillance

67 Case 2 65 yo man presents with PSA 7.2 (3.0 previous year), clinical stage T1c, and Gleason score 4+3=7 prostate cancer. Bone scan and CT scan are negative. Health is excellent. Best treatment choice is: 1. 3D-Conformal Radiation + Brachytherapy yr ADT 2. 3D-Conformal Radiation yr ADT 3. 3D-Conformal Radiation mo ADT 4. Brachytherapy 5. Radical Prostatectomy

68 Case 2 70 yo man presents with PSA 6.2 (3.0 previous year), clinical stage T1c, and Gleason score 4+3=7 prostate cancer. Bone scan and CT scan are negative. Health is excellent. Best treatment choice is: 1. 3D-Conformal Radiation 2. 3D-Conformal Radiation yr ADT 3. 3D-Conformal Radiation mo ADT 4. 3D-Conformal Radiation + Brachytherapy 5. Brachytherapy 6. Radical Prostatectomy

69 2011 Take Home Points 1. Optimal use of PSA should reduce CaP mortality by 50% while avoiding over-treatment 2. Active surveillance monitoring needs to be more rigorous but exactly how remains unclear 3. Men with asymptomatic or minimally symptomatic CRPC may wish to try sipuleucel-t 4. Men who fail docetaxel may wish to try cabazitaxel 5. Denosumab may be superior to zoledronic acid to prevent skeletal-related events