Understanding the risk of recurrence after primary treatment for prostate cancer. Aditya Bagrodia, MD

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1 Understanding the risk of recurrence after primary treatment for prostate cancer Aditya Bagrodia, MD

2 Outline and objectives Prostate cancer demographics Treatment options for patients with newly diagnosed prostate cancer (brief) Predicting outcomes after prostatectomy Predicting outcomes after radiotherapy Predicting outcomes after investigative treatments (brief) HIFU, cryotherapy, Novel platforms to aid in predicting outcomes

3 Carcinoma of Prostate Most common cancer in United States with exception of skin cancer Increases in new cases by 50% between 1980 and 1990 New cases in ,280 (Est.), 80 % early disease Deaths 27,360 (Est.) Increasing number of non-lethal tumors being diagnosed 1 in 6 will be diagnosed, 1 in 35 will die from it. (10% of cancer related deaths in men.)

4 Survival Rates Prostate Cancer 5-year relative survival rate nearly 100% 10-year relative survival rate is 91% 15 year relative survival rate is 76%

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6 Risk Factors for Prostate Cancer Age Rare before 40; 65% over the age of 65 Race - More common in African-American men; more likely diagnosed at advanced stage; 2x more likely to die of the disease; less common in Asian-American and Hispanic-American men than non-hispanic whites. Family History - 1st degree relatives, father, brother Nationality - North America and NW Europe vs Asia, Africa, Central and South America Genetics BRCA1 and BRCA2 increase risk, but account for very small percentage of prostate cancer Obesity, Diet, Exercise, prostatitis, STDs, Vasectomy not much effect, BUT.

7 Presentation/Diagnosis Patient referred to urology for elevated PSA or abnormal digital rectal exam (DRE) Prostate biopsy performed Information available: Clinical exam (DRE), PSA, Gleason score

8 RISK STRATIFICATION The core of the Panel s risk-grouping is the original low-, intermediate-, and high-risk grouping as proposed by D Amico et al. We further augmented the D Amico criteria by subcategorizing the low-risk group into very low- and lowrisk based on criteria analogous to that first proposed by Epstein. Prostate Cancer Severity Amount of Prostate Cancer on Biopsy PSA (ng/ml); PSAD Clin Stage (DRE) Pathology Grade Very Low Risk <1/3 of cores; <50% per core <10; <0.15 Low Risk Any <10;any psad T1-T2a Gleason score <6 (Grade Group 1) D Amico 1998, Epstein 1994

9 CARE OPTIONS VERY LOW-/LOW RISK Very Low Risk Low Risk PSA <10 ng/ml AND Grade Group 1 AND clinical stage T1-T2a AND <34% of biopsy cores positive AND no core with >50% involved, AND PSA density <0.15 ng/ml/cc PSA <10 ng/ml AND Grade Group 1 AND clinical stage T1-T2a 6. Clinicians should not perform abdomino-pelvic CT or routine bone scans in the staging of asymptomatic very low- or low-risk localized prostate cancer patients. (Strong Recommendation; Evidence Level: Grade C)

10 CARE OPTIONS VERY LOW-/LOW RISK 7. Clinicians should recommend active surveillance as the best available care option for very low-risk localized prostate cancer patients. (Strong Recommendation; Evidence Level: Grade A) 8. Clinicians should recommend active surveillance as the preferable care option for most low-risk localized prostate cancer patients. (Moderate Recommendation; Evidence Level: Grade B) Klotz 2015

11 CARE OPTIONS VERY LOW-/LOW RISK 9. Clinicians may offer definitive treatment (i.e. radical prostatectomy or radiotherapy) to select low-risk localized prostate cancer patients who may have a high probability of progression on active surveillance. (Conditional Recommendation; Evidence Level: Grade B) The rationale for electing definitive treatment in low-risk men is based on the fact that even men with low-risk disease face a small chance of metastasis or prostate cancer specific mortality on active surveillance with data from long term studies finding this occurrence to be roughly 3%. (Klotz 2015) ProtecT, Donovan Hamdy 2016

12 CARE OPTIONS VERY LOW-/LOW RISK 10. Clinicians should not add ADT along with radiotherapy for low-risk localized prostate cancer with the exception of reducing the size of the prostate for brachytherapy. (Strong Recommendation; Evidence Level: Grade B) 11. Clinicians should inform low-risk prostate cancer patients considering whole gland cryosurgery that consequent side effects are considerable and survival benefit has not been shown in comparison to active surveillance. (Conditional Recommendation; Evidence Level: Grade C) 12. Clinicians should inform low-risk prostate cancer patients who are considering focal therapy or high intensity focused ultrasound (HIFU) that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion) Donovan 2016

13 CARE OPTION SUMMARY VERY LOW/ LOW Evidence Level/ Recommendation Strength Prostate Cancer Severity/Aggressiveness Very Low Risk Low Risk A / Strong Active Surveillance NA B / Moderate NA Active Surveillance B / Conditional NA Radical Prostatectomy OR Radiotherapy C / Conditional NA Cryosurgery (whole gland) No evidence / clinical principle or expert opinion NA Focal Ablative Therapy OR HIFU

14 RISK STRATIFICATION The Panel incorporated contemporary Grade Group categorizations to subcategorize intermediate-risk group into favorable (Gleason 3+4, Grade Group 2) and unfavorable (Gleason 4+3, Grade Group 3) categories to facilitate decision-making Gleason Score Grade Group* , 5+4, or *Grade Group = Contemporary Pathology Consensus Based on Gleason Score and Adopted by WHO, 2016 Zumsteg 2013, 2016; Mathieu 2017

15 FAVORABLE VS UNFAVORABLE INTERMEDIATE RISK SUB-GROUPS PCa Intermediate Risk Sub-Group Pathology Grade Group PSA (ng/ml) Favorable (3+4=7) <10 Clin Stage (DRE) T1-T2a Unfavorable 2 (3+4=7) <10 T2b 2 (3+4=7) Any T1-2 2 (4+3=7) <20 Any T1-2 (Amount of Pca on biopsy not included in sub-categorization due to lack of such strata in RCT evidence) Zumsteg 2013, 2016; Mathieu 2017

16 CARE OPTIONS INTERMEDIATE RISK Intermediate Risk PSA 10-<20 ng/ml OR Grade Group 2-3 OR clinical stage T2b-c Favorable: Grade Group 1 (with PSA 10-<20) OR Grade Group 2 (with PSA<10) Unfavorable: Grade Group 2 (with either PSA 10-<20 or clinical stage T2b-c) OR Grade Group 3 (with PSA < 20) 15. Clinicians should consider staging unfavorable intermediate-risk localized prostate cancer patients with cross sectional imaging (CT or MRI) and bone scan. (Expert Opinion)

17 CARE OPTIONS INTERMEDIATE RISK 16. Clinicians should recommend radical prostatectomy or radiotherapy plus androgen deprivation therapy (ADT) as standard treatment options for patients with intermediate-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A) Bill-Axelson 2014

18 CARE OPTIONS INTERMEDIATE RISK 17. Clinicians should inform patients that favorable intermediate-risk prostate cancer can be treated with radiation alone, but that the evidence basis is less robust than for combining radiotherapy with ADT. (Moderate Recommendation; Evidence Level: Grade B) Jones 2011

19 CARE OPTIONS INTERMEDIATE RISK 18. In select patients with intermediate-risk localized prostate cancer, clinicians may consider other treatment options such as cryosurgery. (Conditional Recommendation; Evidence Level: Grade C) 19.Active surveillance may be offered to select patients with favorable intermediate-risk localized prostate cancer; however, patients should be informed that this comes with a higher risk of developing metastases compared to definitive treatment. (Conditional Recommendation; Evidence Level: Grade C)

20 CARE OPTIONS INTERMEDIATE RISK 20. Clinicians should recommend observation or watchful waiting for men with a life expectancy 5 years with intermediate-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A) 21. Clinicians should inform intermediate-risk prostate cancer patients who are considering focal therapy or HIFU that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion)

21 CARE OPTION SUMMARY Intermediate Risk Evidence Level/ Recommendation Strength Care Option Advisability Based on Prostate Cancer Severity Subgroup Favorable Unfavorable Intermediate Risk Intermediate Risk A / Strong Radical Prostatectomy OR Radiotherapy with ADT Radical Prostatectomy OR Radiotherapy with ADT B / Moderate Radiotherapy* NA without ADT C / Conditional Active Surveillance OR Cryosurgery (whole gland) Cryosurgery (whole gland) No evidence / clinical principle or expert opinion Focal Ablative Therapy OR HIFU Focal Ablative Therapy OR HIFU * Radiotherapy includes external 3-D conformal or IMRT, alone or combined with LDR or HDR radiotherapy

22 RISK STRATIFICATION High Risk PSA >20 ng/ml OR Grade Group 4-5 OR clinical stage >T3* *Clinical stage T3 cancer is considered locally advanced and, therefore, outside the scope of this guideline. The rationale to not further substratify high-risk men is not based upon differences in outcome, but rather the lack of clinical utility as a context for decisions about treatment options is generally similar between high-risk and very high-risk men.

23 High Risk CARE OPTIONS HIGH RISK PSA >20 ng/ml OR Grade Group 4-5 OR clinical stage >T3* *Clinical stage T3 cancer is considered locally advanced and, therefore, outside the scope of this guideline. 22. Clinicians should stage high-risk localized prostate cancer patients with cross sectional imaging (CT or MRI) and bone scan. (Clinical Principle)

24 CARE OPTIONS HIGH RISK 23. Clinicians should recommend radical prostatectomy or radiotherapy plus androgen deprivation therapy as standard treatment options for patients with high-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A) Bill-Axelson 2014

25 CARE OPTIONS HIGH RISK 24. Clinicians should not recommend active surveillance for patients with high-risk localized prostate cancer. Watchful waiting should only be considered in asymptomatic men with limited life expectancy ( 5 years). (Moderate Recommendation; Evidence Level: Grade C) 25.Cryosurgery, focal therapy and HIFU treatments are not recommended for men with high-risk localized prostate cancer outside of a clinical trial. (Expert Opinion) 26. Clinicians should not recommend primary ADT for patients with high-risk localized prostate cancer unless the patient has both limited life expectancy and local symptoms. (Strong Recommendation; Evidence Level: Grade A)

26 CARE OPTIONS HIGH RISK 27. Clinicians may consider referral for genetic counseling for patients (and their families) with high-risk localized prostate cancer and a strong family history of specific cancers (e.g., breast, ovarian, pancreatic, other gastrointestinal tumors, lymphoma). (Expert Opinion) The Panel recommends that clinicians take detailed family history of cancers and give consideration to patient referral for genetic screening and counseling for men with localized high-risk prostate cancer, particularly in the setting of family history of first degree relatives with cancers of breast, ovary, pancreas, other gastrointestinal cancers, and lymphoma.

27 CARE OPTION SUMMARY HIGH RISK Evidence Level/ Recommendation Strength A / Strong B / Moderate B / Conditional C / Conditional No evidence / clinical principle or expert opinion Prostate Cancer Severity/Aggressiveness High Risk Radical Prostatectomy OR Radiotherapy with ADT NA NA NA NA

28 Scenario update Patient has prostate cancer warranting treatment Appropriate staging (if necessary) performed

29 Options Surgery Radiation

30 Randomization, Treatment, and Follow-up Protect Trial Hamdy FC et al. N Engl J Med DOI: /NEJMoa

31 31 Baseline characteristics stratified by study arm of PROTECT participants

32 Clinical outcomes of men according to treatment arm 21 % 8% 7% 6% 2% 3% 32

33 Surgery: Pre-operative prediction -MSKCC nomograms -Partin Tables du/nomograms/ main.php?nav=4 &audience=1

34 Surgery: Pre-operative prediction Journal of the National Cancer Institute (1998)

35 Surgery: Pre-operative prediction Journal of the National Cancer Institute (1998)

36 Surgery: Pre-operative prediction

37 Surgery: Pre-operative prediction (MSKCC) 62 year old male, PSA 7, T1c, Gleason score 3+4=7, 4/12 cores positive

38 Radiation: Prediction models

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41 Radiation: Prediction models 62 year old male, PSA 7, T1c, Gleason score 3+4=7, 4/12 cores positive External Beam

42 Surgery: Post-operative prediction -MSKCC nomograms du/nomograms/ main.php?nav=4 &audience=1

43 Surgery: Post-operative prediction

44 Surgery: Post-operative prediction (MSKCC) 62 year old male, PSA 7, T3a, negative margins, Gleason score 4+3=7, no lymph node involvement

45 Salvage radiation therapy: Prediction Status update: Our patient 62 year old male, PSA 7, T3a, negative margins, Gleason score 4+3=7, no lymph node involvement has now recurred 2 years later with a PSA of 2 Stephenson AJ, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol May

46 Salvage radiation therapy: Prediction Status update: Our patient 62 year old male, PSA 7, T3a, negative margins, Gleason score 4+3=7, no lymph node involvement has now recurred 2 years later with a PSA of 2

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50 Future directions Incorporation of biomarkers into improving risk prediction

51 TITLE

52 Pricing Summary Oncotype Dx $4180 Medicare: Covered Financial assistance: Available for out of pocket expenses Prolaris $3400 Medicare: Covered Financial assistance: Available if estimated out-ofpocket expenses greater than $375 Decipher $3400 Medicare: Covered Financial assistance: Available and patients pay no more than $295 out-of-pocket

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54 PLOS One 2013;8(6) 545 patients underwent primary RP at Mayo Clinic from 1987 to 2001 Case-Control cohort created with (1) No progression, (2) BCR, (3) Metastasis 213 patients developed metastasis RNA extracted and whole transcriptome 1.4 million RNA expression (44,000 genes) microarray evaluated Differences in RNA expression only found between Group 3 vs the other two Final 22 RNA biomarkers created the Genomic Classifier Final scores range 0 to 1 (higher score with increased probability of metastasis)

55 J Urol 2013;190: patients who underwent primary RP at Mayo Clinic from at high risk of recurrence PSA > 20ng/mL, Gleason > 8, pt3b or Mayo nomogram score >10 Final 219 patients analyzed with 69 developed metastasis High risk group with 93% with Gleason > 7, 47% pt3, 56% +margins

56 GC score separated by low (<0.4), intermediate ( ) and high (>0.6) Development of metastasis 5 years after RP was 2.4%, 6% and 22.5% for the three GC score groups GC was only variable significantly associated with metastasis development MVA: HR 1.51 ( ) p < 0.001

57 JCO 2015;33: patients from Thomas Jefferson (n = 137) and Mayo (n = 51) Patients underwent RP with pt3 or positive surgical margins and received radiation therapy (RT) Adjuvant RT vs Salvage RT based on PSA levels before initiation of RT (< 0.2 ng/ml vs > 0.2 ng/ml) 51% received Adjuvant RT (87% within 12 months of RP) 19 patients developed metastasis after post-rp RT Only 30% received ADT

58 GC was a significant predictor of metastasis UVA: 1.66 ( ) p < MVA: 1.90 ( ) p < Figure B: Cumulative incidence curves stratified by GC to evaluate their prognosis for post-rt metastasis

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61 Clinical Utility Significance: DECIDE Study and PRO-ACT study sought to determine whether Decipher score changed treatment DECIDE found pre-gc and post-gc treatment changed in 43% of adjuvant treatments and in 53% of salvage setting case evaluations PRO-ACT found pre-gc and post-gc adjuvant treatment was modified for 30.8% of patients

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63 Conclusions 1) Once prostate cancer is diagnosed, important to understand the baseline risk and treatment options Surveillance Surgery Radiation Other treatments

64 Conclusions 2) Important to make an informed decision regarding treatment best suited for an individual patient

65 Conclusions 3) Well-calibrated instruments that allow for the prediction of post-treatment outcomes for surgery and radiation 4) Several instruments that allow for outcome prediction if primary treatment fails

66 Conclusions 5) Novel biomarkers may augment our ability to predict response to treatment

67 Thank You! Aditya Bagrodia, MD