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AUA GUIDELINE: ADVANCED PROSTATE CANCER 2020

See 2020 CUA Metastatic Castration-naive and Castration-sensitive Prostate Cancer Guideline Notes

See 2021 CUA CRPC Guideline Notes

See Metastatic Castrate-Sensitive Prostate Cancer Chapter Notes

See CRPC Chapter Notes

Background

• Population covered in this guideline is assumed to have already received local or pelvic therapy, including adjuvant and salvage therapy (i.e., exhaustion of local treatment options).
• For the purpose of this guideline, consider ‘metastatic’ disease based on conventional imaging.
  • Definition of conventional imaging (3):
    1. CT
    2. MRI
    3. Bone scan (99mTc-methylene diphosphonate)
  • Conventional imaging infrequently detect metastases in the setting of early PSA recurrence (e.g., PSA <5 ng/mL).
  • Novel PET-CT scans have higher sensitivity than conventional imaging for the detection of prostate cancer recurrence and metastases at low PSA values (<2.0ng/mL).
    • Oligometastatic disease may be identified, and such patients may be offered management in clinical trials or metastatis-directed surgery.
      • Unknown if earlier identification of metastatic disease with the use of novel PET-CT scans improves overall survival.
  • PET tracers (3):
    1. 18F-fluciclovine
       • Most commonly used radiotracer in the U.S.
       • MOA: images amino acid metabolism.
       • Detection rate appears dependent upon both PSA kinetics and histologic grade.
       • Outperforms standard CT in detection of nodal metastasis
         • Smallest short-axis diameter of nodes exhibiting uptake is 4-9mm, superior to CT.
       • Comparable to standard bone scintigraphy in detection of bone metastases
         • Studies are limited.
       • FDA approved for patients for whom local therapy fails to control disease.
         
    2. Ga-PSMA-11
       • MOA: radiolabeled small molecule that binds to the prostate-specific membrane antigen (PSMA) receptor.
         • PSMA is a transmembrane protein highly overexpressed in >90% of prostate cancers.
       • High specificity and sensitivity
         • Outperforms standard CT and MRI in detection of nodal and osseous metastases.
           • In a recent prospective study of men who had undergone prostatectomy and had a rising PSA still under 2.0ng/mL, PSMA-PET detected occult metastases 4.54x significantly more frequently than fluciclovine-PET§
         • At the time of guideline publication, had not received FDA approval in the U.S. Received FDA approval in December 2020.§
    3. 11C-choline
    • Lower sensitivity and specificity for metastatic disease
    • FDA approved but no longer in routine use for prostate cancer.

Diagnosis and Evaluation

• Recommended
  • Patients diagnosed with aggressive cancer (≥cT3a, Grade Group 4/5, or PSA>20ng/mL) should undergo routine bone scan and cross sectional imaging (CT or MRI) at the time of diagnosis.
  • Discuss treatment options with advanced prostate cancer patients based on life expectancy, comorbidities, preferences, and tumor characteristics, ideally in a multidisciplinary setting.
  • Tissue diagnosis from the primary tumor or site of metastases should be obtained, when clinically feasible, in patients with suspicion of advanced prostate cancer and no prior histologic confirmation.
    • May guide management, even though the clinical picture is often consistent with the diagnosis
      • PARP inhibitors require the identification of mutations in DNA repair genes
      • PD-1/PD-L1 inhibitors require the identification of mutations in mismatch repair (MMR) gene defects leading to microsatellite instability.
      • Biopsy may reveal evidence of neuroendocrine differentiation.
    • Biopsy of the metastatic deposit may be optimal; however, biopsy of the primary tumor may be all that is available.
    • If the patient cannot tolerate biopsy or there is no accessible tissue, treatment may proceed in the absence of histological confirmation.

Biochemical recurrence (“rising PSA”) without metastatic disease after exhaustion of local treatment

• Definition of biochemical recurrence: rise in PSA in prostate cancer patients after treatment with surgery or radiation
  • PSA ≥0.2ng/mL and a confirmatory value of ≥0.2ng/mL following radical prostatectomy
  • Nadir + 2.0ng/mL following radiation
• Risk factors for biochemical recurrence (also risk factors for clinical recurrence) (3):
  1. Grade
  2. Stage
  3. Pre-treatment PSA
• Inform patients with biochemical recurrence after exhaustion of local therapy regarding the risk of developing metastatic disease
  • Given the indolent nature of some cancers, not all patients with a detectable PSA following primary treatment are destined to experience clinical recurrence or cancer-related death.
    • See Pound et al. study
• Management
  • First-line: observation or clinical trial
    • Lack of evidence for optimal treatment approach
    • Currently no systemic treatments with proven efficacy in men without metastatic disease who are not candidates for additional local therapy.
      • For most men with a biochemical recurrence following prostatectomy, early salvage radiotherapy with or without adjuvant ADT remains the preferred treatment strategy.
    • The overall course of a rising PSA after failure of local therapy is highly variable
      • Time to PSA recurrence and PSA doubling-time are associated with risk of subsequent metastases, prostate cancer-related death, and death from any cause.
  • Not recommended: ADT
  • Should not be routinely initiated
    • Two large observational studies found no difference in mortality in patients treated with immediate vs. deferred ADT for biochemical recurrence.
    • It is recognized that ADT is sometimes given to men with rapid PSA rises in the absence of radiographic metastases in an attempt to delay the appearance of metastases. There is no evidence to determine the best time to start ADT in the absence of radiographic metastases.
    • If ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT.
  • Follow-up
    • History and Physical
    • Labs: serial PSA
      • PSA kinetics contribute to the risk of clinical recurrence.
    • Imaging:
      • Based on overall PSA and PSA kinetics
        • Higher risk of metastases (PSADT <12 months): periodic staging with cross-sectional imaging (CT, MRI) and technetium bone scan.
          • Novel PET-CT scans may be useful in patients with PSA recurrence after failure of local therapy as an alternative to conventional imaging or in the setting of negative conventional imaging.

Metastatic hormone-sensitive prostate cancer (mHSPC)

• Definition of HSPC: prostate cancer that has either not yet been treated with ADT or is still responsive to ADT as manifested by the absence of clinical progression, radiographic progression, or a rising PSA of ≥2.0 ng/mL above nadir.
  • Also be referred to as castrate-sensitive prostate cancer, endocrine-sensitive prostate cancer, and hormone-naïve prostate cancer.
• Categorize patients as de novo metastatic or having progression in stage after prior failed treatment.
  • De novo metastatic disease is present at the time of initial prostate cancer diagnosis rather than recurring after previous treatment of localized cancer
    • Associated with poorer prognosis than recurrent disease.
  Diagnosis and Evaluation
  • History and Physical Exam
    • Presence of symptoms from metastatic disease
      • Symptoms in mHSPC have been shown to have prognostic value.
  • Imaging
    • Assess the extent of metastatic disease (bone, lymph node and visceral metastasis) using conventional imaging in newly diagnosed mHSPC
      • Extent of metastatic disease influences response.
      • 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
  • Genetic counseling and germline testing, regardless of age and family history
• Management
  • First-line: Continuous ADT in combination with either (4):
    1. Abiraterone acetate plus prednisone
    2. Apalutamide
    3. Enzalutamide
    4. Docetaxel
    • No comparative data on efficacy exist between these 4 options.
    • See Metastatic Castrate-Sensitive Prostate Cancer Chapter Notes for details on trials
  • Primary radiotherapy to the prostate
    • May be offered in selected mHSPC patients with low-volume (STAMPEDE definition) metastatic disease.
    • See Metastatic Castrate-Sensitive Prostate Cancer Chapter Notes for details on trials
  • ADT
    • Castrate levels of testosterone (<50ng/dL) may be achieved with:
      • LHRH agonists
      • GnRH antagonists
      • Surgical castration
    • GnRH antagonists and orchiectomy as monotherapy have a rapid onset of action and avoid the ‘testosterone flare’ seen with LHRH analogues alone making them useful in situations needing rapid hormone ablation such as impending spinal cord compression.
    • First generation antiandrogens (bicalutamide, flutamide, nilutamide) should not be used in combination with LHRH agonists in patients with mHSPC, except to block testosterone flare.
      • In the first week after LHRH agonists are administered, there is typically a surge in LH resulting in an increase in circulating testosterone. This may cause clinical “flares,” which may be associated with worsening of disease symptoms (e.g., bone pain, urinary tract obstruction) in approximately 10% of patients. This surge can be “blocked” by short term (i.e., 4 weeks or less) of a first-generation antiandrogen
    • Insufficient evidence to support the use of first generation antiandrogens as monotherapy.
  • Oral androgen pathway directed therapy
    • Includes abiraterone acetate plus prednisone, apalutamide, bicalutamide, darolutomide, enzalutamide, flutamide, nilutamide)
    • Should not be offered without ADT
      • All of the data suggesting that additional therapy (chemotherapy or androgen receptor-targeted therapy [ART]) significantly improves OS was in the context of continuous ADT; the Panel generally advises against intermittent ADT in otherwise healthy patients with mHSPC.
  • Follow-up
    • Obtain a baseline PSA and serial PSAs at 3-6 month intervals after initiation of ADT and consider periodic conventional imaging.
      • PSA at 3-6 month intervals allows for determination of the nadir and risk group stratification
        • PSA nadir after 6 months of ADT in newly diagnosed metastatic prostate cancer patients has been shown to be prognostic for survival.
      • PSA is also used in identifying CRPC
      • PSA alone is not completely predictive of cancer progression as some patients may demonstrate cancer growth in the absence of a PSA rise (e.g. poorly differentiated, ductal, and neuroendocrine tumors as well as mCRPC).
        • Symptom assessment is an important
        • Periodic imaging is reasonable to assess disease stability.
          • No set interval for imaging of men with mHSPC.
    • Periodic testosterone measurement may also be used to confirm response to ADT.

Castration-resistant prostate cancer (CRPC)

• Definition of CRPC: disease progression despite ADT and a castrate level of testosterone (<50 ng/dL).
  • Progression may present as either (3):
    1. Continuous rise in PSA
       • Prostate Cancer Working Group definition: values identified at a minimum of 1 week intervals with a minimal value of 2.0ng/mL, with estimations of PSA doubling time [PSADT] with at least 3 values measured ≥4 weeks apart)
    2. Radiographic progression of pre-existing or new radiographic disease
    3. Clinical progression with symptoms.

Non-metastatic castration-resistant prostate cancer (nmCRPC)

• Novel PET-CT scans have allowed for the discovery of small volume metastases that were previously undetected with conventional imaging. Nevertheless, there remains a subset of patients whose disease remains defined by biochemical PSA rise only.
• Management:
  • PSADT >10 months: observation with continuous ADT
  • High risk for developing metastatic disease (PSADT ≤10 months): continuous ADT with either (3):
    1. Apalutamide
    2. Darolutamide
    3. Enzalutamide
    • Bicalutamide is no longer a viable strategy for treatment of this patient population.
  • PSADT is useful in determining which men are at highest risk of developing metastatic lesions or dying from prostate cancer.
    • Calculate a PSADT starting at the time of development of castration-resistance by obtaining serial PSA measurements at 3-6-month intervals
  • PSADT <10 months
    • Used to identify the highest risk population for inclusion in the 3 trials that led to approval of the AR antagonists for men with nmCRPC
      • FDA approval based on superiority in terms of prolonging MFS by nearly 2 years.
        • The use of MFS rather than OS as a regulatory endpoint is novel in solid tumors, and was partially based on the Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) meta-analysis of 19 clinical trials demonstrating that MFS is a surrogate for OS for men with localized prostate cancer.
    • Recommended to consider when adding one of the medications to ADT in men with nmCRPC. However, FDA approval of these agents does not specify a doubling time.
  • Systemic chemotherapy or immunotherapy should not be used in nmCRPC patients outside the context of a clinical trial.
  • Follow-up:
  • Conventional imaging q6-12 months to assess for development of metastatic disease
    • In patients with mCRPC treated with enzalutamide prior to chemotherapy in the PREVAIL trial, radiographic progression occurred in 24.5% of patients without PSA progression, suggesting that routine imaging can identify a significant portion of patients with radiographic progression who would otherwise not be identified. This principle is extrapolated to the nmCRPC population, particularly for men on additional AR antagonist treatment.

Metastatic castration-resistant prostate cancer (mCRPC)

• Diagnosis and Evaluation
  • History and Physical Exam
    • Performance status and the extent of disease-related symptoms are strongly associated with mortality.
  • Labs
    • PSA, testosterone, LDH, Hgb, alkaline phosphatase
    • Laboratory risk-factors associated with increasing risk of mortality include elevated LDH, testosterone <20-50ng/dL, higher PSA, and shorter PSADT.
  • Imaging
    • Assess extent of metastatic disease (bone, lymph node, visceral)
      • Increasing burden of metastatic disease in the form of the number of metastatic sites is associated with increasing risk of overall mortality.
      • Visceral metastases are known to portend the highest risk of mortality, followed by bone, compared to lymph nodes
    • Assess the extent of metastatic disease using conventional imaging at least annually or at intervals determined by lack of response to therapy.
      • In patients with mCRPC treated with enzalutamide prior to chemotherapy in the PREVAIL trial, radiographic progression occurred in 24.5% of patients without PSA progression, suggesting that routine imaging can identify a significant portion of patients with radiographic progression who would otherwise not be identified.
  • Germline and somatic tumor genetic testing
    • May inform prognosis and counseling regarding family risk as well as potential targeted therapies by identifying DNA repair deficiency mutations and microsatellite instability status.
• Management
  • Primary therapy (5):
    • First-line: continuous ADT with either (3):
      1. Abiraterone acetate plus prednisone (Grade A)
      2. Enzalutamide (Grade A)
      3. Docetaxel (Grade B)
    • Other options (2):
      1. Sipuleucel-T
         • May be offered to patients who are asymptomatic or minimally symptomatic
           • Not recommended in symptomatic disease that necessitates opioid use
         • Not associated with objective anti-tumor activity; not appropriate for patients with large tumor burdens, those with visceral disease or with rapidly progressive disease.
      2. Radium-223
      • Should be offered to patients with symptoms from bony metastases from mCRPC and without known visceral disease or lymphadenopathy >3cm.
      • MOA: an α-emitting radiopharmaceutical
        • Capable of inducing double strand DNA breaks in cancer cells while minimizing exposure to surrounding marrow.
        • The use of radium-223 for the treatment of bone metastases relies on the chemical similarity to calcium and the ability of the α-radiation and the short-lived decay products of radium-223 to kill cancer cells.
      • Adverse events include neutropenia and thrombocytopenia
      • Targets bone only and is not associated with a PSA decline in a majority of patients; therefore imperative to carefully assess the patient on a monthly basis.
        • Progression in non-bone sites is not infrequent during this 6-month period of treatment.
        • Given the lack of utility of PSA measurement in this space, the Panel recommends consideration to obtain abdomen/pelvis CT imaging and chest x-ray even in the absence of symptoms prior to cycle 4 (of planned 6 monthly cycles) to assess for occult disease progression.
  • Secondary therapy
    • Should favor treatments that have a different mechanism of action than what was used previously.
      • Abiraterone acetate plus prednisone followed by enzalutamide would be the favored sequence in mCRPC if both agents were used.
    • Cabazitaxel
      • May be offered if received prior docetaxel chemotherapy (with or without prior abiraterone acetate plus prednisone or enzalutamide).
      • Recommended over an alternative androgen pathway directed therapy if prior docetaxel chemotherapy and abiraterone acetate plus prednisone or enzalutamide
    • Mitoxantrone
    • Not associated with a survival benefit
  • Other therapies
    • PARP inhibitor
      • Should be offered to patients with deleterious or suspected deleterious germline (e.g. BRCA1, BRCA2, ATM, etc.) or somatic homologous recombination repair gene-mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy.
    • Defects in DNA repair occur in up to 30% of men with mCRPC, and such cancer cells depend instead on PARP-regulated DNA repair. Therefore, inhibition of PARP in these tumors results in cell death
    • Options: olaparib and rucaparib
    • Platinum based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor.
    • Pembrolizumab
      • Shoud be offered in patients with mismatch repair deficient or microsatellite instability-high mCRPC.
        • In a case series of 1,033 patients with advanced prostate cancer, 3.1% had a microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) prostate cancer, with more than half of those treated with anti PD-1 therapy responding to treatment having a >50% decline in PSA.
  • Bone health
    • Risk factors for bone complications in patients with metastatic prostate cancer (3):
      1. Age-related decreases in bone mineral density
      2. ADT is associated with progressive loss of bone mineral density
      3. Bones are the most common site of metastatic disease
    • Risk of osteoporosis associated with ADT should be discussed
    • Diagnosis and Evaluation
      • Assess the risk of fragility fracture in patients with advanced prostate cancer.
        • The Fracture Risk Assessment Tool is a validated resource to help predict a patient’s 10-year probability of hip fracture and the 10-year probability of a major osteoporotic-related fracture (spine, forearm, hip or shoulder fracture). This tool can be used with or without measurement of bone mineral density.
          
      • Baseline bone mineral density measurement with dual x-ray absorptiometry (DXA) may be considered in men receiving ADT and other systemic treatments for prostate cancer.
        • The largest decrease in bone mineral density occurs within the first year of therapy
          • Reasonable to re-assess osteoporotic-related risk (FRAX® and DXA) 1-year after initiating systemic treatment, and at longer intervals thereafter.
    • Management
      • Preventative treatment for fractures and skeletal-related events (3):
        1. Supplemental calcium and vitamin D
           • Estimated daily calcium requirement is 1,000-1,200 mg from food and supplements.
           • Estimated daily vitamin D requirement is 1,000 IU from food, supplements, and sunlight.
        2. Smoking cessation
        3. Weight-bearing exercise
        • Insufficient evidence to inform the optimal strategies for the prevention of bone loss and frailty fractures.
      • Pharmacologic strategies for osteoporosis prevention and treatment (2):
        1. Bisphosphonates
           • Oral bisphosphonates (e.g., alendronate, pamidronate)
           • Intravenous bisphosphonates (e.g., zoledronic acid)
           • Amongst bisphosphonates, the greatest reduction in fractures was observed for zoledronic acid
        2. Subcutaneous RANK ligand inhibitors (e.g., denosumab).
        • The recommended dose and treatment schedules for zoledronic acid and denosumab are different for the indications of osteoporotic fracture prevention and skeletal-related event prevention.
          • For example, zoledronic acid is usually administered yearly for osteoporosis-related fracture prevention compared to monthly or every three months for metastatic cancer skeletal-related event prevention. Similarly, denosumab has been administered as 60mg every 6 months for osteoporosis compared to 120mg monthly for skeletal-related event prevention.
        • Because men who need dental extractions while on zoledronic acid or denosumab are at higher risk for ONJ, clinicians should consider evaluation by a dentist prior to initiation.
      • In advanced prostate cancer patients at high fracture risk due to bone loss, preventative treatment with a bone-protective agent (denosumab or zoledronic acid) is recommended and referral to physicians who have familiarity with the management of osteoporosis when appropriate.
      • In mCRPC patients with bone metastases, a bone-protective agent (denosumab or zoledronic acid) is recommended to prevent skeletal-related events.
        • In mCRPC, zoledronic acid has been shown to
          1. Lower rates of skeletal-related events
          2. Increase time to first skeletal-related event
          3. Decrease rate of pathologic fracture
        • Denosumab vs. zoledronic acid
          • Non-inferiority trial of 1,904 men with mCRPC with bone metastases
          • Randomized to receive denosumab or zoledronic acid
          • Primary outcome: time to skeletal-related event.
          • Results:
            • Denosumab non-inferior to zoledronic acid for the primary endpoint of outcome of time to SRE
            • Denosumab was superior to zoledronic acid in improving time to first skeletal-related event in a secondary analysis (p = 0.008).
            • Rates of hypocalcemia were higher with denosumab than zolendronic acid; as such, clinicians should monitor calcium levels prior to infusions, and repletion of vitamin D prior to starting these agents, along with calcium and vitamin D maintenance.
          • Fizazi, Karim, et al."Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study." The Lancet 377.9768 (2011): 813-822.
        • CALGB 90202
          • Early treatment with zoledronic acid in men with mHSPC and bone metastases was not associated with lower risk for SREs or death.

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