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AUA: Advanced Prostate Cancer (2023): Difference between revisions

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'''See [https://www.auanet.org/guidelines-and-quality/guidelines/advanced-prostate-cancer Original Guidelines]'''
'''See [https://www.auanet.org/guidelines-and-quality/guidelines/advanced-prostate-cancer Original Guidelines]'''
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'''See [[Castrate-Resistant Prostate Cancer|CRPC Chapter Notes]]'''
'''See [[Castrate-Resistant Prostate Cancer|CRPC Chapter Notes]]'''
'''See [[Hormonal Therapy|Hormonal Therapy Chapter Notes]]'''


== Background ==
== Background ==
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***#** Studies are limited.
***#** Studies are limited.
***#* '''FDA approved for patients for whom local therapy fails to control disease.'''
***#* '''FDA approved for patients for whom local therapy fails to control disease.'''
***# '''<span style="color:#ff0000">Ga-PSMA-11</span>'''
***# '''<span style="color:#ff0000">68Ga-PSMA-11</span>'''
***#* '''<span style="color:#ff0000">MOA:</span>''' radiolabeled small molecule that '''<span style="color:#ff0000">binds to the prostate-specific membrane antigen (PSMA) receptor.</span>'''
***#* '''<span style="color:#ff0000">MOA:</span>''' radiolabeled small molecule that '''<span style="color:#ff0000">binds to the prostate-specific membrane antigen (PSMA) receptor.</span>'''
***#** '''<span style="color:#ff0000">PSMA is a transmembrane protein highly overexpressed in >90% of prostate cancers.</span>'''
***#** '''<span style="color:#ff0000">PSMA is a transmembrane protein highly overexpressed in >90% of prostate cancers.</span>'''
***#* '''<span style="color:#ff0000">High specificity and sensitivity</span>'''
***#* '''<span style="color:#ff0000">High specificity and sensitivity</span>'''
***#** '''<span style="color:#ff0000">Outperforms standard CT and MRI in detection of nodal and osseous metastases.</span>'''
***#** '''<span style="color:#ff0000">Outperforms standard CT and MRI in detection of nodal and osseous metastases.</span>'''
***#*** 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§
***#*** 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[https://pubmed.ncbi.nlm.nih.gov/31375469/ §]
***#** At the time of guideline publication, had not received FDA approval in the U.S. '''Received FDA approval''' in December 2020.§
***#** At the time of guideline publication, had not received FDA approval in the U.S. '''Received FDA approval''' in December 2020.[https://www.fda.gov/news-events/press-announcements/fda-approves-first-psma-targeted-pet-imaging-drug-men-prostate-cancer §]
***# '''<span style="color:#ff0000">11C-choline</span>'''
***# '''<span style="color:#ff0000">11C-choline</span>'''
***#* '''Lower sensitivity and specificity for metastatic disease'''
***#* '''Lower sensitivity and specificity for metastatic disease'''
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***'''Biopsy of the metastatic deposit may be optimal;''' however, biopsy of the primary tumor may be all that is available.
***'''Biopsy of the metastatic deposit may be optimal;''' however, biopsy of the primary tumor may be all that is available.
*'''May guide management''', even though the clinical picture is often consistent with the diagnosis
*'''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'''
** '''PARP inhibitors (olaparib, rucaparib) 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.'''
** '''PD-1/PD-L1 inhibitors (pembrolizumab) require the identification of mutations in mismatch repair (MMR) gene defects leading to microsatellite instability.'''
** '''Biopsy may reveal evidence of neuroendocrine differentiation.'''
** '''Biopsy may reveal evidence of neuroendocrine differentiation.'''


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** 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.
** 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 [https://test.urologyschool.com/index.php/Biochemical_Recurrence#Natural_history Pound et al. study]
*** See [https://test.urologyschool.com/index.php/Biochemical_Recurrence#Natural_history Pound et al. study]
* '''<span style="color:#ff0000">Management</span>'''
 
** '''<span style="color:#ff0000">First-line: observation or clinical trial</span>'''
=== <span style="color:#ff0000">Diagnosis and Evaluation</span> ===
*** 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.'''
* '''<span style="color:#ff0000">PSMA PET imaging should be used preferentially, where available, in patients with PSA recurrence after failure of local therapy as an alternative to conventional imaging due to its greater sensitivity, or in the setting of negative conventional imaging</span>'''
**** 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'''
=== <span style="color:#ff0000">Management</span> ===
**** '''Time to PSA recurrence and PSA doubling-time are associated with risk of subsequent metastases, prostate cancer-related death, and death from any cause.'''
* '''<span style="color:#ff0000">First-line: observation or clinical trial</span>'''
** '''<span style="color:#ff0000">Not recommended: ADT</span>'''
** Lack of evidence for optimal treatment approach
*** '''<span style="color:#ff0000">Should not be routinely initiated</span>'''
** '''Currently no systemic treatments with proven efficacy in men without metastatic disease who are not candidates for additional local therapy.'''
**** Two large observational studies found no difference in mortality in patients treated with immediate vs. deferred ADT for biochemical recurrence.
*** For most men with a biochemical recurrence following prostatectomy, early salvage radiotherapy with or without adjuvant ADT remains the preferred treatment strategy.
**** 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.
** '''The overall course of a rising PSA after failure of local therapy is highly variable'''
**** '''If ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT.'''
*** '''Time to PSA recurrence and PSA doubling-time are associated with risk of subsequent metastases, prostate cancer-related death, and death from any cause.'''
* '''<span style="color:#ff0000">Follow-up</span>'''
* '''<span style="color:#ff0000">Not recommended: ADT</span>'''
** '''<span style="color:#ff0000">History and Physical</span>'''
** '''<span style="color:#ff0000">Should not be routinely initiated</span>'''
** '''<span style="color:#ff0000">Labs: serial PSA</span>'''
*** Two large observational studies found no difference in mortality in patients treated with immediate vs. deferred ADT for biochemical recurrence.
*** <span style="color:#ff0000">PSA kinetics contribute to the risk of clinical recurrence.</span>
*** 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.
** '''<span style="color:#ff0000">Imaging:</span>'''
*** '''If ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT.'''
*** '''<span style="color:#ff0000">Based on overall PSA and PSA kinetics</span>'''
 
**** '''<span style="color:#ff0000">Higher risk of metastases (PSADT <12 months): periodic staging with cross-sectional imaging (CT, MRI) and technetium bone scan.</span>'''
* Follow-up
***** '''<span style="color:#ff0000">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.</span>'''
** 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, and/or preferably PSMA PET imaging


== Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) ==
== Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) ==
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*** Symptoms in mHSPC have been shown to have prognostic value.
*** Symptoms in mHSPC have been shown to have prognostic value.
* '''<span style="color:#ff0000">Imaging</span>'''
* '''<span style="color:#ff0000">Imaging</span>'''
** '''<span style="color:#ff0000">Assess the extent of metastatic disease (bone, lymph node and visceral metastasis) using conventional imaging in newly diagnosed mHSPC</span>'''
** '''<span style="color:#ff0000">Assess the extent of metastatic disease (lymph node, bone, and visceral metastasis) in newly diagnosed mHSPC</span>'''
*** Extent of metastatic disease influences response.
*** Extent of metastatic disease influences response.
*** '''<span style="color:#ff0000">CHAARTED definition of high-volume vs. low-volume</span>'''
*** '''<span style="color:#ff0000">CHAARTED definition of high-volume vs. low-volume</span>'''
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****# '''<span style="color:#ff0000">Gleason score ≥ 8</span>'''
****# '''<span style="color:#ff0000">Gleason score ≥ 8</span>'''
**** LATITUDE excluded patients with “Low-risk” disease
**** LATITUDE excluded patients with “Low-risk” disease
* '''<span style="color:#ff0000">Genetic counseling and germline testing,</span>''' regardless of age and family history
* '''<span style="color:#ff0000">Genetic testing</span>'''
**'''<span style="color:#ff0000">Offer germline testing</span>'''
**'''<span style="color:#ff0000">Consider somatic testing and genetic counseling</span>'''


=== <span style="color:#ff0000">Management</span> ===
=== <span style="color:#ff0000">Management</span> ===
* '''<span style="color:#ff0000">First-line: Continuous ADT in combination with either (4):</span>'''
* '''<span style="color:#ff0000">First-line: ADT in combination with either (4):</span>'''
*# '''<span style="color:#ff0000">Abiraterone acetate plus prednisone</span>'''
*# '''<span style="color:#ff0000">Abiraterone acetate plus prednisone</span>'''
*# '''<span style="color:#ff0000">Enzalutamide</span>'''
*# '''<span style="color:#ff0000">Enzalutamide</span>'''
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** '''<span style="color:#ff0000">May be offered in selected mHSPC patients with low-volume (CHAARTED definition) metastatic disease.</span>'''
** '''<span style="color:#ff0000">May be offered in selected mHSPC patients with low-volume (CHAARTED definition) metastatic disease.</span>'''
** '''See [[Metastatic Hormone-Sensitive Prostate Cancer|Metastatic Hormone-Sensitive Prostate Cancer Chapter Notes]]  for details on trials'''
** '''See [[Metastatic Hormone-Sensitive Prostate Cancer|Metastatic Hormone-Sensitive Prostate Cancer Chapter Notes]]  for details on trials'''
* '''ADT'''
* '''De Novo mHSPC'''
** '''In selected patients with de novo mHSPC, clinicians should offer ADT in combination with docetaxel and either abiraterone acetate plus prednisone or darolutamide.'''
*'''ADT'''
** Castrate levels of testosterone (<50ng/dL) may be achieved with:
** Castrate levels of testosterone (<50ng/dL) may be achieved with:
*** LHRH agonists
*** LHRH agonists
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*** 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.
*** 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 ===
* '''Follow-up'''
* '''Obtain a baseline PSA and serial PSAs at 3-6 month intervals after initiation of ADT and consider periodic conventional imaging.'''
** '''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 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 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 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).
*** '''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'''
**** '''Symptom assessment is an important'''
*** '''Periodic imaging is reasonable to assess disease stability.'''
**** '''Periodic imaging is reasonable to assess disease stability.'''
**** No set interval for imaging of men with mHSPC.
***** No set interval for imaging of men with mHSPC.
* '''Periodic testosterone measurement may also be used to confirm response to ADT.'''
** '''Periodic testosterone measurement may also be used to confirm response to ADT.'''


== Castration-resistant prostate cancer (CRPC) ==
== Castration-Resistant Prostate Cancer (CRPC) ==


* '''<span style="color:#ff0000">Definition of CRPC: disease progression despite ADT and a castrate level of testosterone (<50 ng/dL).</span>'''
* '''<span style="color:#ff0000">Definition of CRPC: disease progression despite ADT and a castrate level of testosterone (<50 ng/dL).</span>'''
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* '''<span style="color:#ff0000">High risk for developing metastatic disease (PSADT ≤10 months): continuous ADT with either (3):</span>'''
* '''<span style="color:#ff0000">High risk for developing metastatic disease (PSADT ≤10 months): continuous ADT with either (3):</span>'''
*# '''<span style="color:#ff0000">Apalutamide</span>'''
*# '''<span style="color:#ff0000">Apalutamide</span>'''
*# '''<span style="color:#ff0000">Darolutamide</span>'''
*# '''<span style="color:#ff0000">Enzalutamide</span>'''
*# '''<span style="color:#ff0000">Enzalutamide</span>'''
*#'''<span style="color:#ff0000">Darolutamide</span>'''
** Bicalutamide is no longer a viable strategy for treatment of this patient population.
** 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.
* PSADT is useful in determining which men are at highest risk of developing metastatic lesions or dying from prostate cancer.
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*** 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.
*** 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.
* Systemic chemotherapy or immunotherapy should not be used in nmCRPC patients outside the context of a clinical trial.
*'''Follow-up'''
**'''Conventional or PSMA PET 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 ====
===== UrologySchool.com Summary =====
* '''<span style="color:#ff0000">History and Physical Exam'''
**'''<span style="color:#ff0000">Performance status'''
**'''<span style="color:#ff0000">Symptoms'''
* '''<span style="color:#ff0000">Labs (5):'''
*# '''<span style="color:#ff0000">PSA'''
*# '''<span style="color:#ff0000">Testosterone'''
*# '''<span style="color:#ff0000">LDH'''
*# '''<span style="color:#ff0000">Hemoglobin'''
*# '''<span style="color:#ff0000">Alkaline phosphatase'''
* '''<span style="color:#ff0000">Imaging'''
** '''<span style="color:#ff0000">Assess extent of metastatic disease (bone, lymph node, visceral)'''
* '''<span style="color:#ff0000">Other (1):'''
** '''<span style="color:#ff0000">Germline and somatic tumor genetic testing'''
===== 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:
**Higher PSA
**Shorter PSADT
**Elevated LDH
**Testosterone <20-50ng/dL
===== 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 =====
* To identify DNA repair deficiency, microsatellite instability (MSI) status, tumor mutational burden, and other potential mutations that may inform prognosis and familial cancer risk, as well as direct potential targeted therapies.
==== Management ====
===== Primary Therapy =====
* '''<span style="color:#ff0000">Patients who have not received prior androgen receptor pathway inhibitors</span>'''
* '''<span style="color:#ff0000">Options (5):</span>'''
**'''<span style="color:#ff0000">First-line: continuous ADT with either (3):</span>'''
**# '''<span style="color:#ff0000">Abiraterone acetate plus prednisone (Grade A)</span>'''
**# '''<span style="color:#ff0000">Enzalutamide (Grade A)</span>'''
**# '''<span style="color:#ff0000">Docetaxel (Grade B)</span>'''
** '''<span style="color:#ff0000">Other options (2):</span>'''
**# '''<span style="color:#ff0000">Sipuleucel-T</span>'''
**#* '''<span style="color:#ff0000">May be offered to patients who are asymptomatic or minimally symptomatic'''
**#** '''Not recommended in symptomatic disease that necessitates opioid use</span>'''
**#* Not associated with objective anti-tumor activity; not appropriate for patients with large tumor burdens, those with visceral disease or with rapidly progressive disease.
**# '''<span style="color:#ff0000">Radium-223</span>'''
**#* '''<span style="color:#ff0000">Should be offered to patients with symptoms from bony metastases from mCRPC and without known visceral disease or lymphadenopathy >3cm.</span>'''
**#* '''<span style="color:#ff0000">MOA: an α-emitting radiopharmaceutical</span>'''
**#** 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.
**#* <span style="color:#ff0000">'''Adverse events include neutropenia and thrombocytopenia'''</span>
**#* '''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.


==== Follow-up ====
===== Secondary Therapy =====
* '''Conventional imaging q6-12 months to assess for development of metastatic disease'''
* '''Should favor treatments that have a different mechanism of action than what was used previously.'''
** 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.
** '''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


=== Metastatic castration-resistant prostate cancer (mCRPC) ===
===== Other Therapies =====
* '''<span style="color:#ff0000">PARP inhibitor</span>'''
** '''<span style="color:#ff0000">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</span> 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
** '''<span style="color:#ff0000">Options: olaparib and rucaparib</span>'''
** Platinum based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor.
* '''<span style="color:#ff0000">Pembrolizumab</span>'''
** '''<span style="color:#ff0000">Should be offered in patients with mismatch repair deficient or microsatellite instability-high mCRPC.</span>'''
*** 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.


* '''Diagnosis and Evaluation'''
===== Bone health =====
** '''History and Physical Exam'''
* Risk factors for bone complications in patients with metastatic prostate cancer (3):
*** '''Performance status and the extent of disease-related symptoms''' are strongly associated with mortality.
*# Age-related decreases in bone mineral density
** '''Labs'''
*# ADT is associated with progressive loss of bone mineral density
*** '''PSA, testosterone, LDH, Hgb, alkaline phosphatase'''
*# Bones are the most common site of metastatic disease
*** Laboratory risk-factors associated with increasing risk of mortality include elevated LDH, testosterone <20-50ng/dL, higher PSA, and shorter PSADT.
* Risk of osteoporosis associated with ADT should be discussed
** '''Imaging'''
* '''<span style="color:#ff0000">Diagnosis and Evaluation</span>'''
*** '''Assess extent of metastatic disease (bone, lymph node, visceral)'''
** '''<span style="color:#ff0000">Assess the risk of fragility fracture in patients with advanced prostate cancer.</span>'''
**** Increasing burden of metastatic disease in the form of the number of metastatic sites is associated with increasing risk of overall mortality.
*** 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.
**** Visceral metastases are known to portend the highest risk of mortality, followed by bone, compared to lymph nodes
** '''<span style="color:#ff0000">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.</span>'''
*** '''Assess the extent of metastatic disease using conventional imaging at least annually or at intervals determined by lack of response to therapy.'''
*** '''The largest decrease in bone mineral density occurs within the first year of 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.
**** Reasonable to re-assess osteoporotic-related risk (FRAX® and DXA) 1-year after initiating systemic treatment, and at longer intervals thereafter.
** '''Germline and somatic tumor genetic testing'''
* '''<span style="color:#ff0000">Management</span>'''
*** May inform prognosis and counseling regarding family risk as well as potential targeted therapies by identifying DNA repair deficiency mutations and microsatellite instability status.
** '''<span style="color:#ff0000">Preventative treatment for fractures and skeletal-related events (3):</span>'''
* '''Management'''
**# '''<span style="color:#ff0000">Supplemental calcium and vitamin D</span>'''
** '''Primary therapy (5):'''
**#* Estimated daily calcium requirement is 1,000-1,200 mg from food and supplements.
*** '''First-line: continuous ADT with either (3):'''
**#* Estimated daily vitamin D requirement is 1,000 IU from food, supplements, and sunlight.
***# '''Abiraterone acetate plus prednisone (Grade A)'''
**# '''<span style="color:#ff0000">Smoking cessation</span>'''
***# '''Enzalutamide (Grade A)'''
**# '''<span style="color:#ff0000">Weight-bearing exercise</span>'''
***# '''Docetaxel (Grade B)'''
*** Insufficient evidence to inform the optimal strategies for the prevention of bone loss and frailty fractures.
*** '''Other options (2):'''
** '''<span style="color:#ff0000">Pharmacologic strategies for osteoporosis prevention and treatment (2):</span>'''
***# '''Sipuleucel-T'''
**# '''<span style="color:#ff0000">Bisphosphonates</span>'''
***#* '''May be offered to patients who are asymptomatic or minimally symptomatic'''
**#* '''<span style="color:#ff0000">Oral bisphosphonates (e.g., alendronate, pamidronate)</span>'''
***#** '''Not recommended in symptomatic disease that necessitates opioid use'''
**#* '''<span style="color:#ff0000">Intravenous bisphosphonates (e.g., zoledronic acid)</span>'''
***#* Not associated with objective anti-tumor activity; not appropriate for patients with large tumor burdens, those with visceral disease or with rapidly progressive disease.
**#* Amongst bisphosphonates, the greatest reduction in fractures was observed for zoledronic acid
***# '''Radium-223'''
**# '''<span style="color:#ff0000">Subcutaneous RANK ligand inhibitors (e.g., denosumab).</span>'''
***#* '''Should be offered to patients with symptoms from bony metastases from mCRPC and without known visceral disease or lymphadenopathy >3cm.'''
*** 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.
***#* '''MOA: an α-emitting radiopharmaceutical'''
**** 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.
***#** Capable of inducing double strand DNA breaks in cancer cells while minimizing exposure to surrounding marrow.
*** '''<span style="color:#ff0000">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.</span>'''
***#** 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.
** '''<span style="color:#ff0000">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.</span>'''
***#* Adverse events include neutropenia and thrombocytopenia
** '''<span style="color:#ff0000">In mCRPC patients with bone metastases, a bone-protective agent (denosumab or zoledronic acid) is recommended</span>''' to prevent skeletal-related events.
***#* '''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.'''
*** In mCRPC, zoledronic acid has been shown to
***#** Progression in non-bone sites is not infrequent during this 6-month period of treatment.
***# Lower rates of skeletal-related events
***#** 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.
***# Increase time to first skeletal-related event
** '''Secondary therapy'''
***# Decrease rate of pathologic fracture
*** '''Should favor treatments that have a different mechanism of action than what was used previously.'''
*** '''Denosumab vs. zoledronic acid'''
**** '''Abiraterone acetate plus prednisone followed by enzalutamide would be the favored sequence in mCRPC if both agents were used.'''
**** Non-inferiority trial of 1,904 men with mCRPC with bone metastases
*** '''Cabazitaxel'''
**** Randomized to receive denosumab or zoledronic acid
**** '''May be offered if received prior docetaxel chemotherapy (with or without prior abiraterone acetate plus prednisone or enzalutamide).'''
**** Primary outcome: time to skeletal-related event.
**** '''Recommended over an alternative androgen pathway directed therapy if prior docetaxel chemotherapy and abiraterone acetate plus prednisone or enzalutamide'''
**** Results:
*** Mitoxantrone
***** Denosumab non-inferior to zoledronic acid for the primary endpoint of outcome of time to SRE
**** Not associated with a survival benefit
***** Denosumab was superior to zoledronic acid in improving time to first skeletal-related event in a secondary analysis (p = 0.008).
** '''Other therapies'''
***** '''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.'''
*** '''PARP inhibitor'''
**** 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.
**** '''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.'''
*** CALGB 90202
**** 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
**** Early treatment with zoledronic acid in men with mHSPC and bone metastases was not associated with lower risk for SREs or death.
**** '''Options: olaparib and rucaparib'''
*'''Follow-up'''
**** Platinum based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor.
**In mCRPC patients without PSA progression or new symptoms, clinicians should perform imaging at least annually.
*** '''Pembrolizumab'''
**'''<span style="color:#ff0000">In mCRPC patients with disease progression (PSA or radiographic progression or new disease-related symptoms) having previously received docetaxel and androgen pathway inhibitor, 177Lu-PSMA-617 should be offered</span>'''
**** '''Shoud be offered in patients with mismatch repair deficient or microsatellite instability-high mCRPC.'''
***PSMA PET imaging should be offered in patients who are considering 177Lu-PSMA-617
***** 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):
***# Age-related decreases in bone mineral density
***# ADT is associated with progressive loss of bone mineral density
***# 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):'''
****# '''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.
****# '''Smoking cessation'''
****# '''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):'''
****# '''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
****# '''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
*****# Lower rates of skeletal-related events
*****# Increase time to first skeletal-related event
*****# 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.


== References ==
== References ==
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