Editing AUA: Advanced Prostate Cancer (2023) (section)

== 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">Progression may present as either (3):</span>'''
**# '''<span style="color:#ff0000">Continuous rise in PSA</span>'''
**#* '''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)'''
**# '''<span style="color:#ff0000">Radiographic progression</span>''' of pre-existing or new radiographic disease
**# '''<span style="color:#ff0000">Clinical progression</span>''' 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 ====
* '''<span style="color:#ff0000">PSADT >10 months: observation with continuous ADT</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">Enzalutamide</span>'''
*#'''<span style="color:#ff0000">Darolutamide</span>'''
** 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 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.

===== 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 =====
* '''<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.

===== 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
* '''<span style="color:#ff0000">Diagnosis and Evaluation</span>'''
** '''<span style="color:#ff0000">Assess the risk of fragility fracture in patients with advanced prostate cancer.</span>'''
*** 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.
** '''<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>'''
*** '''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.
* '''<span style="color:#ff0000">Management</span>'''
** '''<span style="color:#ff0000">Preventative treatment for fractures and skeletal-related events (3):</span>'''
**# '''<span style="color:#ff0000">Supplemental calcium and vitamin D</span>'''
**#* 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.
**# '''<span style="color:#ff0000">Smoking cessation</span>'''
**# '''<span style="color:#ff0000">Weight-bearing exercise</span>'''
*** Insufficient evidence to inform the optimal strategies for the prevention of bone loss and frailty fractures.
** '''<span style="color:#ff0000">Pharmacologic strategies for osteoporosis prevention and treatment (2):</span>'''
**# '''<span style="color:#ff0000">Bisphosphonates</span>'''
**#* '''<span style="color:#ff0000">Oral bisphosphonates (e.g., alendronate, pamidronate)</span>'''
**#* '''<span style="color:#ff0000">Intravenous bisphosphonates (e.g., zoledronic acid)</span>'''
**#* Amongst bisphosphonates, the greatest reduction in fractures was observed for zoledronic acid
**# '''<span style="color:#ff0000">Subcutaneous RANK ligand inhibitors (e.g., denosumab).</span>'''
*** 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.
*** '''<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>'''
** '''<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>'''
** '''<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.
*** 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.
*'''Follow-up'''
**In mCRPC patients without PSA progression or new symptoms, clinicians should perform imaging at least annually.
**'''<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>'''
***PSMA PET imaging should be offered in patients who are considering 177Lu-PSMA-617