What’s new in prostate cancer part 2, 2021

How to make treatment decisions about prostate cancer, When is watchful waiting appropriate and how to chose between radiation or surgery.

1. Some questions about Prostate Cancer Part 2 2021 Robert Miller MD

2. Deciding on Treatment for Prostate Cancer in 2021 You need to find current, accurate and trustworthy sources of information. The most comprehensive, reliable site that is updated continuously is hosted by the National Comprehensive Cancer Network or NCCN and I encourage everyone to start there first (https://www.nccn.org/ or https://www.nccn.org/patientresources/patient-resources )

3. NCCN.org

4. https://www.nccn.org

5. ​ www.aboutcancer.com tinyurl.com/ robertmillermd www.youtube.com/c/RobertMillerMD

6. Bladder Prostate Urethra Cancer Prostate View from the front, notice the overlap with the bladder and urethra

7. Prostate View from the side Close proximity to major structures makes surgery or radiation risky sphincter

8. Why is the management of prostate cancer still controversial? Because many cases grow too slowly to affect the patient so there is no justification to risk the possible side effects of treatment in every case. Need to understand the biology of the cancer to predict its behavior and balance that with the man’s health, longevity and interest in considering therapy.

9. https://gis.cdc.gov/Cancer/USCS/DataViz.html At 5 Years almost everyone with prostate cancer is still alive So no value in using 5 years stats to compare treatments

10. Prostate Stage Distribution of SEER Incidence Cases, 2009-2018 Stage at Diagnosis Percent of cases Localized 73.3 Regional 12.4 Distant 6.3 Prostate Recent Trends in SEER Relative Survival Rates, 2000-2018 All 96.5% Localized 100% Regional 99.6% Distant 39.8% https://seer.cancer.gov/explorer Male By Race/Ethnicity, All Ages, 5 years 85% of cases are diagnosed at local or regional stage and their relative 5-year survival is close to 100%

11. Prostate Stage Distribution of SEER Incidence Cases, 2009-2018 Stage at Diagnosis Percent of cases Localized 73.3 Regional 12.4 Distant 6.3 Prostate Recent Trends in SEER Relative Survival Rates, 2000-2018 All 96.5% Localized 100% Regional 99.6% Distant 39.8% https://seer.cancer.gov/explorer Male By Race/Ethnicity, All Ages, 5 years 6% present with metastases but even in this group 40% are alive at 5 years New and improved hormone therapy drugs are extending survival from three years out to 4 or 5 years in this group

12. 12.5% 2.4% 6.1% 4.5% https://seer.cancer.gov/explorer

13. 39% 19%

14. https://seer.cancer.gov/explorer/ 12.5% 2.4% 60-70’s 80-90’s

15. Cancer Median Age at Diagnosis Median Age at Death All 66 (M) 65 (F) 72 (M) 73 (F) Breast 68 (M) 63 (F) 70 (M) 69 (F) Colon 67 (M) 70 (F) 70 (M) 75 (F) Lung 70 (M) 71 (F) 71 (M) 73 (F) Prostate 67 (W) 64 (B) 81 (W) 76 (B) SEER Median Age of Cancer Patients at Diagnosis a , 2014-2018 By Primary Cancer Site, Race and Sex https://seer.cancer.gov/csr/1975_2018/browse_csr.php?sectionSEL=1&pageSEL=sect_01_table.11 Median Age of Cancer Patients at Death a , 2014-2018 6 – 8 years 2 – 6 years 3 -5 years 1 – 2 years 12 – 14 years

16. Final Guidance on Metastasis-Free Survival in nmCRPC (non-metastatic castrate resistant prostate cancer) Released by the FDA / August 9, 2021 Because overall survival comparisons may take years to show a benefit, they may be willing to approve a new drug if the study shows that it prevents or delays the development of metastases.

17. Things that might affect the decision to treat one you’ve made the diagnosis of cancer Biology and extent of the cancer (how aggressive and how advanced) Health status of the patient (general state of health, other disease problems, life expectancy, personal goals)

18. Top 25 th Percentile Median Bottom 25 th Percentile

19. https://www.ssa.gov/oact/STATS/table4c6_2016.html + or – by 50% based on health status

20. FDA Approves First PSMA-Targeted PET Imaging Drug for Men with Prostate Cancer For Immediate Release: December 01, 2020

21. PSMA is better than Fluciclovine ( Axumin ) PET Scans

22. Biology : The more mutated the cancer cells the lower the cure rate 88% if well differentiated cells 70% if moderate differentiated cells 50% if poorly differentiated cells

23. Cancer Grade or Gleason Score , the more poorly differentiated ( mutated ) the worse the outcome

24. Risk of Relapse Based on Gleason Grade Group Grade Group Relapse at 5 Years 1 4% 2 12% 3 37% 4 52% 5 74% Relapse may just mean that the PSA blood test which went back to normal after treatment, starts rising again.

25. Extra Biomarkers May Help Better Predict Low Risk or High-Risk Behavior Would it be safe to hold off on any initial treatments and just monitor the cancer for months (or even years)?

26. In 2018 the NCCN Included Genomics in the Decision Process

27. Genomic test evaluates the activity of genes in the tumor that are shown to be involved in the development and progression of prostate cancer.

28. Risk of Metastases using Combined System Spratt Journal of Clinical Oncology  36, no. 6, 2018 Clear separation between risk groups and outcome Intermediate High Low

29. Risk of Metastases using Combined System 10 Year Risk of Mets Very-low 3.1% Low 3.7% Favor Intermed 25.9% Unfav Intermed 31.7% High 49.7% Very High 61.9% Spratt Journal of Clinical Oncology  36, no. 6, 2018

30. 10 Year Risk of Metastases Very-low 3.1% Low 3.7% Favor Intermed 25.9% Unfav Intermed 31.7% High 49.7% Very High 61.9% How is this Helpful? Do Less Therapy Do More Therapy Do A lot More Therapy Bone mets

31. Low Risk : observation (short life expectancy) or active surveillance (long life expectancy) e.g. Gleason 6 and PSA below 10 Intermediate Risk : active surveillance (short life expectancy) or curative local therapy (surgery or radiation) e.g Gleason 6 or 7 and PSA 10 - 20 High Risk : surgery or radiation possibly combined with hormone therapy or chemotherapy. e.g. Gleason 8 or higher or PSA > 20 Metastatic : hormone therapy but also other options (including chemotherapy, immunotherapy, isotope therapy)

32. Should I hold off on initial treatment?

33. If you decide to Treat, which is better, surgery or radiation? For surgery: “high volume surgeons in high volume centers generally provide better outcomes” For radiation “highly conformal techniques with daily prostate localization” is optimal

34. External Beam Radiation Therapy Usually daily (M:F) for 4 to 8 weeks ( photons or protons ) but newer techniques can complete in just 5 treatments

35. Brachytherapy (seeds or wires) One or two treatments, sometimes combined with external in high-risk patients

36. Trends in Diagnosis and Disparities in Initial Management of High-Risk Prostate Cancer in the US JAMA Netw Open.  2020;3(8):e2014674 The NCDB was queried to identify men with high-risk prostate cancer from 2004 to 2016. Radiation Surgery IMRT (radiation) or Robotic Laparoscopic (surgery) now about equal choices

37. Are there studies comparing men who proceed directly to treatment ( surgery or radiation ) versus men who hold off and just do surveillance ? Are we sure it is safe to wait and hold off initially or is there a big chance that the cancer will progress and become incurable during the watchful waiting period? Prostate Cancer Intervention versus Observation Trial ( PIVOT )

38. Prostate Cancer Intervention versus Observation Trial ( PIVOT ) From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation at Department of Veterans Affairs and National Cancer Institute medical centers localized prostate cancer (stage T1-T2NxM0 of any grade diagnosed within the previous 12 months. Patients had to have a PSA value of less than 50 ng per milliliter, an age of 75 years or younger, negative results on a bone scan for metastatic disease, and a life expectancy of at least 10 years. N Engl J Med 2017; 377:132-142

39. Follow-up of Prostatectomy versus Observation for Early Prostate Cancer / N Engl J Med 2017; 377:132-142 Long term survival not affected by delaying or avoiding treatment Even just looking at deaths from prostate cancer there was very little harm due to delaying or avoiding treatment

40. Follow-up of Prostatectomy versus Observation for Early Prostate Cancer / N Engl J Med 2017; 377:132-142 Cumulative Incidence of Death from Prostate Cancer through 19.5 Years. Group Prostatectomy Observation Low risk 0.9% 6.6% Intermediate 9.0% 8.6% High Risk 12.8% 23.5% Only high-risk patients need to start treatment immediately

41. 24% eventually treated So, 76% avoided ever getting treated Radical prostatectomy Observation

42. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer . Hamdy NEJM 2016;375:1415 Prostate Testing for Cancer and Treatment ( ProtecT ) Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545) The median age of the participants was 62 years (range, 50 to 69), the median PSA level at the prostate-check clinic was 4.6 ng per milliliter (range, 3.0 to 19.9), 77% had tumors with a Gleason score of 6 Triggers to reassess patients and consider a change in clinical management were based largely on changes in PSA levels Randomized Trial between Surgery or Radiation or Monitoring

43. 54% of monitoring group were eventually treated

44. Results at 10 Years Variable Monitoring Surgery Radiation Prostate Survival 98.8% 99.0% 99.6% Survival Great in all three groups More likely to progress in the monitor arm

45. Randomized Trial between Surgery or Radiation…Surgery and Radiation same cure rate ProtecT Trial, NEJM 2016;375:1415 Even at 10 years the results with surgery or radiation were the same

46. Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer/ ProtecT Study Group N Engl J Med 2016; 375:1425-1437 Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer | NEJM Surgery worst Surgery worst

47. Cure Rates with Radiation versus Surgery for Early-Stage Prostate Cancer are the same from the Cleveland Clinic.  Kupelian . JCO Aug 15 2002: 3376-3385 Cleveland Clinic Study out to 8 Years and basically same outcome between radiation or surgery

48. Same 10 Year Survival with very high Gleason (score of 9 – 10) Kishan JAMA 2018;319:895 Even with High Gleason Score (high-risk cancer) the 10-year results were the same

49. 10 Year Cure Rates for Patients with High-Risk Prostate Cancer (PSA >20 or Gleason 8-10 or T3) Treatment Number Cure Rate Radical Prostatectomy 1,238 92% Radiation plus Hormones 344 92% Radiation alone 265 88% Mayo Clinic Study ( Boorjian Cancer 117;2883, 2011) Same results in Mayo Clinic study but the radiation patients generally require hormone therapy which has its own side effects which many men object to

50. Patient-Reported Outcomes Through 5 Years for Active Surveillance, Surgery, Brachytherapy, or External Beam Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer January 14, 2020 JAMA.  2020;323(2):149-163 prospective, population-based study of 1386 men with favorable-risk prostate cancer and 619 men with unfavorable -risk prostate cancer,   age, 64 [59-70 ] treatments (favorable-risk disease: active surveillance, nerve-sparing prostatectomy, external beam radiation therapy, or low-dose-rate brachytherapy; unfavorable-risk disease: prostatectomy or external beam radiation therapy with androgen deprivation therapy measured with Expanded Prostate Cancer Index Composite scores, attenuated over time with no clinically meaningful bowel or hormonal functional differences at 5 years. However, prostatectomy was associated with worse incontinence over 5 years (adjusted mean difference of –10.9 for favorable-risk disease and −23.2 for unfavorable-risk disease) and worse sexual function at 5 years for unfavorable-risk disease (adjusted mean difference, −12.5).

51. Side Effects Initially surgery worse By 5 years radiation was worst (many also had hormone therapy)

52. surgery worse

53. Initially seeds worst

54. Initially seeds worst

55. Charles B Huggins Awarded the 1966 Nobel Prize for Physiology or Medicine for discovering in 1941 that hormones could be used to control the spread of prostate cancer. This was the first discovery that showed that cancer could be controlled by chemicals.   DES (diethylstilbestrol) a synthetic form of estrogen discovered in 1938

56. Strategies of Hormone Therapy for Prostate Cancer Interfere at the pituitary level Interfere at the adrenal gland level Interfere at the testicle level Interfere at the cell receptor level

57. Androgens  include androstenediol (A5), androstenedione (A4), dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), androsterone, and testosterone. These  androgens  become activated when bound to  androgen receptors . In males,  androgens  are produced in the testes (95%) and the adrenal glands.

58. 5 Types of Endocrine therapy (LHRH agonists, LHRH antagonists, 1 st gen antiandrogen, 2 nd gen antiandrogen, androgen biosynthesis inhibitors) Multiple chemotherapy drugs ( cabazitaxel and docetaxel) Two types of immunotherapy ( sipuleucel -T or pembrolizumab ) PARP inhibitors ( olaparib ) Isotope Therapy (Ra 223 Xofigo ) Any new drugs since DES? ….2021 List

59. LHRH agonists Goserelin ( Zoladex ) Histrelin ( Supprelin ) Leuprolide (Lupron) Triptorelin (Trelstar) LHRH antagonists Degarelix (Firmagon) First generation antiandrogens Nilutamide ( Nilandron ) Flutamide ( Eulexin ) Bicalutamide ( Casodex ) Second generation antiandrogens Enzalutamide (Xtandi) Apalutamide ( Erleada ) Darolutamide ( Nubeqa ) Androgen biosynthesis inhibitor Abiraterone (Zytiga) Endocrine Therapy for Prostate Cancer

60. Multiple Sites of Action for Apalutamide (second generation androgen receptor blocker)

61. Spartan Trial / failed surgery or radiation and now had rising PSA despite Lupron, if they then added in Apalutamide , marked delay in progression. NEJM 2018 / Feb 8 Metastasis-Free Survival

62. Study adding Nubeqa to hormone therapy in men whose PSA was rising again despite remaning on hormone therapy (castrate resistant, non-metastatic)

63. Overall Survival in LATITUDE Updated Analysis

64. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. James. NEJM 2017;377. STAMPEDE Trial

65. Other Options to Endocrine Therapy with a microsatellite instability-high (also known as MSI-H) or a mismatch repair deficient ( dMMR ) biomarker

66. Isotope Therapy Against Prostate Cancer

67. Radioactive isotope attached to the peptide, releases gamma ray for SPECT imaging and beta particles that will kill the cancer Peptide designed to attach to the target receptors on the cancer cells

68. Attach to the receptors on the surface of the cell Gets inside Beta radiation kills the cancer

69. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer NEJM / June 23, 2021 https://www.nejm.org/doi/full/10.1056/NEJMoa2107322 Prostate-specific membrane antigen (PSMA ) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 ( 177 Lu)–PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment. phase 3 trial evaluating  177 Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 ( 68 Ga)–labeled PSMA-11 positron-emission tomographic–computed tomographic scans. Radioligand therapy with  177 Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival 

70. FDA Approves First PSMA-Targeted PET Imaging Drug for Men with Prostate Cancer For Immediate Release: December 01, 2020

71. Progression-free survival Overall Survival

72. Lutetium-177–PSMA-617 PET Scan results before and after treatments

73. Treatment Algorithm I nitial approach to treatment of metastatic and nonmetastatic castration-resistant prostate cancer These need to be computerized and driven by AI (though Watson was considered a failure) Its failed partnership with MD Anderson Cancer Center in 2017 brought a fresh wave of criticism to the business, and in April 2019, IBM announced it was winding down  Watson's  work on AI-enabled drug discovery due to poor financial returns.

74. https://www.nccn.org

75. ​ www.youtube.com/c/RobertMillerMD

76. https://www.mskcc.org/nomograms/prostate Calculate the outcome from a radical prostatectomy for 75 yo man with Gleason 7 / T1c / PSA 6 / 4 + core biopsies By 10 years after surgery 41% had a recurrence by at 15 years the chance of dying of prostate cancer was only 1% Using Nomograms

77. https://www.mskcc.org/nomograms/prostate Calculate the outcome from a radical prostatectomy for 60 yo man with Gleason 8 / T2b / PSA 20 / 6 + core biopsies By 10 years after surgery 88% had a recurrence by at 15 years the chance of dying of prostate cancer was only 4%

78. https://prostate.predict.nhs.uk/tool

79. https://umich-biostatistics.shinyapps.io/star-cap/ STAR CAP Prostate Cancer Staging System Our staging model is for patients diagnosed with prostate cancer who have not yet begun treatment. We predict the long-term chances of dying from prostate cancer  with standard curative treatments  including surgical removal of the prostate gland or curative radiation therapy with or without hormonal therapy. Metric Prediction Stage IIB 5-Year Prostate Cancer Specific Mortality 1.1% 10-Year Prostate Cancer Specific Mortality 4.4% This patient is 65 years old with clinical T1c N0 M0 prostate adenocarcinoma, Gleason 4+3 with 6/12 (50%) core biopsies positive, and a PSA of 12 ng/ mL. This patient is NCCN risk group Unfavorable Intermediate. This patient is grouped in STAR CAP Stage IIB.

80. How to think about prostate cancer treatment in 2021 May want to review the current NCCN guidelines (ideally with your doctor) to feel confident in understanding the biology of your specific cancer Meet with both a surgeon ( Urologist ) and a Radiation Oncologist to hear their recommendations and to get a better understanding of the risks and side effects associated with the various treatment options For high risk or metastatic cancers, you may want to also meet with a Medical Oncologist to get an opinion about the place of chemotherapy, hormone therapy or other options (e.g. immunotherapy) or to consider whether a clinical research trial would be an option. Both modern radiation and robotic surgery are highly technical , and the best outcome and lowest risk of complications accrue from being treated by a doctor or center that has the most modern equipment (image guided IMRT) and expertise (how many robotic cases has he/she performed) in treating prostate cancer, so spend the time to do some research on the qualifications of your doctors….(you may need a couple of ‘second’ opinions) Or…you may trust your doctor and let him tell you what to do and just stay out of it.

81. Or…you may trust your doctor and let him/her tell you what to do and just stay out of it.

82. www.youtube.com/c/RobertMillerMD tinyurl.com/ robertmillermd