CUA: Metastatic Castration-naive and Castration-sensitive Prostate Cancer (2020)

See Metastatic Castrate-Sensitive Prostate Cancer Chapter Notes

Background

• In Canada, ≈8% of men present with metastatic disease at the time of prostate cancer (PC) diagnosis
• Median OS in men presenting with de novo metastatic PC: ≈3-4 years
  • Metastatic disease at presentation is associated with a worse prognosis compared to metastatic disease that develops after diagnosis
• The mainstay of treatment for de novo metastatic PC is androgen deprivation therapy (ADT) which is initially effective in almost all patients.
• The development of androgen-deprivation therapy (ADT) resistance (i.e., cancer progression despite castrate levels of serum testosterone i.e. castrate-resistant prostate cancer) is a virtually universal state that affects all prostate cancer patients treated with ADT.
• For this guideline, databases were accessed to identify all relevant articles focused on mCNPC or mCSPC between January 2000 and August 2019 [and therefore may not include more recent data]

Clinical Staging

• Indications
  • For newly diagnosed PC, staging with CT scan of the abdomen and pelvis and bone scan (99mTc-MDP) should be performed for men with ANY high-risk feature (3):
    1. PSA>20 ng/mL
    2. Gleason score >7
    3. Clinical stage T3 or greater
    • Note that the 2017 AUA Guidelines on Localized Prostate Cancer recommend staging in some intermediate-risk (2/3 of the following: palpable tumour on DRE, Gleason 7, and PSA > 10) and all high-risk patients
• Modalities
  • Conventional staging imaging includes (2):
    1. Bone scintigraphy using technetium-99mmethylene diphosphonate (99mTc-MDP) to assess for bone metastases
    2. Adominopelvic CT imaging to assess for lymphadenopathy and visceral metastases.
    • In patients with high risk disease, CT imaging of the chest may also be considered as lung metastases are the most common site of visceral metastases.
  • Novel diagnostic imaging to stage PC including choline-based PET/CT, fluciclovine PET/CT and PSMA-targeted PET/CT, appear to improve the sensitivity and specificity of conventional imaging; however, these tests are not universally available in Canada

Assessment of Prognosis

• Men with mCNPC/mCSPC should be assessed in a multidisciplinary manner whenever possible
• Patients should be classified as high volume/high risk or low volume/low risk based on conventional imaging and prostate cancer biopsy for prognostication
• See Metastatic Castrate-Sensitive Prostate Cancer Chapter Notes for details on CHAARTED and LATITUDE
  • CHAARTED definition of high-volume vs. low-volume
    • High-volume:
      • Visceral metastasis or
      • ≥4 bone metastases with ≥ 1 beyond the vertebral bodies and pelvis
    • Low-volume: all others
  • LATITUDE definition of high-risk vs. low-risk
    • High-risk: ≥2 of the following 3 criteria:
      1. Visceral metastases
      2. ≥ 3 bony metastases
      3. Gleason score ≥ 8
    • LATITUDE excluded patients with “Low-risk” disease

Management

• UrologySchool.com summary:
  • All patients: ADT (LHRH analogue) + Calcium + Vitamin D
    • Bisphosphonates in patients at high-risk of fracture
  • Additional treatment based on high vs. low-volume/risk
    • Local treatment
      • EBRT for low-volume
    • Systemic treatment
      • Any volume of disease: enzalutamide, apalutamide
      • High-volume: docetaxel
      • Low-volume: docetaxel, consider abiraterone
      • High-risk: abiraterone, consider docetaxel
      • Note that there has been no trial involving "low-risk" mCRPC patients

• Androgen-deprivation therapy
  • ADT should be started on men newly diagnosed with metastatic PC
  • Continuous ADT is the standard of care while intermittent may be considered in select patients
    • Intermittent ADT should only be used as an exception in select patients with close follow-up; combined treatment of mCNPC with any systemic therapy requires continuous ADT
    • See Hormonal Therapy Chapter Notes for details on intermittent ADT

• Local therapy: Treatment of the primary cancer in mCNPC
  • Low-volume disease: consider external beam radiation therapy (EBRT) to the prostate (Level of evidence 2, Strong recommendation).
    • Treatment of the primary PC has theoretical benefits, including reducing local side effects that may occur due to disease progression during mCRPC and well as removing the cancer that could be source of cytokines and growth factors that may induce disease progression.
    • Two recent randomized trials assessed the impact of EBRT in mCNPC: STAMPEDE and HORRAD trial
      • [In both trials], EBRT improved failure-free survival (FFS) but not OS
      • OS improved in EBRT patients with low metastatic burden; no OS benefit in EBRT patients with high metastatic burden
        • Although both trials showed negative impact of EBRT in unselected men in mCNPC, both HORRAD and STAMPEDE reveal the benefits of local therapy in those with low burden disease.
        • The STOPCAP meta-analysis combining data from the trials confirm the benefits of EBRT in men with < 5 bone metastases§
  • Radical prostatectomy in mCNPC should only be performed in a clinical trial setting
    • Currently, there is limited evidence showing the benefit of radical prostatectomy in mCNPC.

• Systemic therapies (4): docetaxel chemotherapy, abiraterone acetate, enzalutamide, and apalutamide
  • Docetaxel (75 mg/m2 every 3 weeks for six cycles):
    • 3 different large randomized trials assessed the impact of introducing docetaxel in mCNPC/mCSPC: CHAARTED, STAMPEDE, and GETUG-AFU
      • Unlike CHAARTED and GETUG-AFU15 trials, patients with high-risk non-metastatic PC were included in the STAMPEDE trial
    • An option for mCNPC/mCSPC men with good performance and high-volume metastatic disease (CHAARTED definition) (Level 1, Strong recommendation)
    • May be an option for mCNPC/mCSPC men with good performance status and low-volume disease (CHAARTED definition) (Level 2, Weak recommendation)
    • May be considered for mCNPC/mCSPC men with good performance status and “high-risk” mCNPC/mCSPC patients (LATITUDE definition) (Level 1, Strong recommendation)
  • Abiraterone acetate (1000mg daily) with prednisone (5mg daily)
    • An option for mCNPC patients with “high-risk” disease (LATITUDE definition) (Level of evidence 1, Strong recommendation)
    • May be considered for patients with low-volume mCNPC (Level of evidence 3, Weak recommendation).
  • Enzalutamide (160mg/day)
    • Two recent studies assessed the role of enzalutamide in mCNPC: ARCHES and ENZAMET
    • An option for mCNPC/mCSPC regardless of volume of disease (Level of evidence 1, Strong recommendation)
    • Should not be used in combination (concurrent use) with docetaxel to treat mCNPC/mCSPC
    • May be considered in mCSPC patients previously treated with docetaxel chemotherapy (sequential use) (Level of evidence 1, Weak recommendation)
  • Apalutamide (240mg/day)
    • An option for men with mCNPC/mCSPC regardless of volume of disease (Level of evidence 1, Strong recommendation).

Prevention of osteoporosis

• All men treated with ADT
  • Require vitamin D supplementation (800-1200IU daily) and calcium supplementation (800mg-1000mg total intake daily).
  • Should be assessed for fracture risk.
    • Bone loss occurs quickly while on ADT and within 1 year; men can lose up to 10% of their bone mineral density (BMD).
    • Men with mCNPC initiating ADT should have baseline BMD with dual-energy x-ray absorptiometry (DXA) as well as utilization of fracture risk calculators such as FRAX.
      • DXA should be performed at least every 2 two years and more often in untreated patients at high risk or if there is a history of osteoporosis/osteopenia.
    • Those at high risk of fractures (DXA scanning shows any evidence of osteopenia (T-score of <-1 and > -2.5) or osteoporosis (T-score of less than -2.5) should start a bone targeted therapy (zoledronic acid 5mg once a year, alendronate 70mg weekly, denosumab 60mg every 6 months) to improve BMD and reduce the risk of fragility fractures.
      • Bone targeted therapy at these doses are much lower than those to prevent SREs in mCRPC
• Lifestyle changes: smoking cessation, reduction in alcohol and caffeine intake and increase weight-bearing exercises.

Treatment of oligo-metastatic disease

• Evolving evidence of the role of radiation to asymptomatic distant metastases, especially in low burden “oligometastatic” disease.
• Currently, limited data to provide general recommendations, however, consideration in a multi-disciplinary setting would provide the best setting to determine optimal management consideration case-by-case.

Questions

1. What proportion of men with prostate cancer present with metastatic disease?
2. Which patients with mCSPC should be considered for EBRT to the prostate?
3. What are the systemic treatment options in mCSPC and which patients should be considered for each?

Answers

1. What proportion of men with prostate cancer present with metastatic disease?
   • 8%
2. Which patients with mCSPC should be considered for EBRT to the prostate?
   • Low-volume mCSPC
3. What are the systemic treatment options in mCSPC and which patients should be considered for each?
   • Options: docetaxel chemotherapy, abiraterone acetate, enzalutamide, and apalutamide
   • Any volume of disease: enzalutamide, apalutamide
   • Low-volume: docetaxel, consider abiraterone
   • High-volume: docetaxel
   • High-risk: abiraterone, consider docetaxel