Editing Castrate-Resistant Prostate Cancer (section)

==== Approach to mCRPC management ====

===== Chemotherapy naïve mCRPC =====

====== Asymptomatic or minimally symptomatic ======
*'''Minimally symptomatic defined as pain that is relieved by acetaminophen or a non-steroidal anti-inflammatory'''
*'''First-line (2):'''
**'''Abiraterone acetate 1000 mg/day plus prednisone 5 mg PO BID OR'''
**'''Enzalutamide 160 mg/day'''
***'''Patients who have had little or no response to hormonal agents OR who progress with minimal change in PSA OR with significant visceral metastases should be considered for early chemotherapeutic options'''
*'''Second-line: Docetaxel (75 mg/m2 every 3 weeks plus prednisone 5 mg PO BID)'''
**The timing of docetaxel therapy in men with evidence of metastases but without symptoms should be individualized based on patients’ clinical status and preferences
** '''Rising PSA only during docetaxel chemotherapy should not be used as the sole criteria for progression; assessment of response should incorporate clinical and radiographic criteria'''

====== Moderate or severe symptoms ======
*'''Docetaxel''' (75 mg/m2 every 3 weeks plus prednisone 5 mg PO BID) '''is recommended'''
* '''Radium-223 every 4 weeks for six cycles is recommended in patients with pain due to bone metastases and who do not have visceral metastases'''
** '''Radium-223 significantly improved overall survival and reduced symptomatic skeletal related events in patients with symptomatic mCRPC who had previously received docetaxel chemotherapy or were deemed unfit for docetaxel'''
* '''Abiraterone''' (1000 mg/day plus prednisone 5 mg twice daily) '''or enzalutamide''' (160mg/day) '''may be considered as first-line therapy in patients who cannot receive or refuse docetaxel'''
** NOTE: The studies in the chemo-naive setting did not include patients with moderate or severe symptoms; however, abiraterone and enzalutamide may be potential therapeutic options in patients who are deemed chemotherapy-ineligible or refuse chemotherapy
* '''Alternative therapies that have not demonstrated improvement in OS but can provide disease control, palliation, and improve quality of life include:'''
** '''Weekly docetaxel plus prednisone'''
** '''Mitoxantrone plus prednisone'''

===== mCRPC who progress after docetaxel-based chemotherapy =====
* '''Options with survival benefit (5):'''
** '''Cabazitaxel''' (25 mg/m2) plus prednisone (5 mg/day) '''TROPIC trial'''
** '''Radium-223 every four weeks for six cycles ALSYMPCA trial'''
** '''If not received prior to docetaxel:'''
*** '''Abiraterone acetate''' (1000 mg per day) '''plus prednisone''' (5 mg twice daily) '''COU-AA-301 trial'''
*** '''Enzalutamide''' (160 mg/day) '''AFFIRM trial'''
* '''Options with unknown survival benefit'''
** '''Docetaxel plus prednisone re-exposure in patients who have had a previous favourable response to docetaxel may be reasonable'''
** '''Mitoxantrone may be considered a therapeutic option in symptomatic patients with mCRPC in the first- or second-line setting. Mitoxantrone has not shown any survival advantage but may provide symptomatic relief'''

===== Other supportive agents =====
* '''Systemic corticosteroid therapy with low-dose prednisone or dexamethasone may also offer improvements in PSA values and/or palliative outcomes in up to 30% of patients in both symptomatic and asymptomatic men.'''
** '''Steroids may also exert an anti-neoplastic effect on prostate cancer'''

===== mCRPC with bone metastasis =====
* '''Denosumab (120 mg subcutaneous) or zoledronic acid (4 mg intravenous) every 4 weeks, along with daily calcium and vitamin D supplementation, is recommended to prevent disease-related skeletal related events'''§
** '''Skeletal related events include (4):'''
**# '''Pathological fractures'''
**# '''Spinal cord compression'''
**# '''Surgery'''
**# '''Radiation therapy to bone'''
** '''Bisphosphonates''' '''-dronate''' (pami'''dronate''', alen'''dronate''', rise'''dronate''', and zole'''dronate''')
*** '''MOA: reduce bone resorption by inhibiting osteoclastic activity and proliferation'''
*** Bisphosphonates other than zoledronic acid are not known to be effective to prevent disease-related SREs.§
*** '''Zoledronate'''
**** '''A potent intravenous bisphosphonate'''
**** '''Indications:'''
***** '''Progressive mCRPC with evidence of bone metastasis.'''
****** '''In a prospective randomized trial of 422 patients with progressive CRPC and bone metastases, zoledronate was shown to reduce the incidence of skeletal-related events (e.g., pain, fractures) compared with placebo (Saad et al, 2004).'''
***** In non-metastatic prostate cancer patients receiving long-term ADT, zoledronate and pamidronate have been shown to '''increase bone mineral density'''
***** '''In hormone-sensitive prostate cancer, STAMPEDE showed that the addition of zoledronic acid did not significantly reduce time to first skeletal-related event compared to ADT alone.''' STAMPEDE showed that docetaxel + ADT had reduced time to first skeletal-related events compared to ADT alone
**** '''Contraindications (1)'''
****# '''Renal impairment'''
****#* '''Should not be used with baseline creatinine clearance <30 mL/min'''
****#* '''Can be dose adjusted for decreased renal function'''
**** '''Adverse events:'''
***** '''Osteonecrosis of the jaw'''
***** '''Hypocalcemia'''
****** '''Concomitant administration of oral calcium supplements (1000 mg/day) and vitamin D (800 units/day) is often recommended.'''
***** '''Fatigue'''
***** '''Myalgias'''
***** '''Fever'''
***** '''Anemia'''
***** '''Mild elevation of serum creatinine'''
** '''Denosumab'''
*** '''MOA: human monoclonal antibody against RANK ligand,''' which mediates osteoclast differentiation and activation
*** '''Improve BMD and decrease risk of vertebral fractures in men with non-metastatic PCa receiving ADT at high risk of fracture§'''
*** '''Denosumab vs. zoledronate in mCRPC'''
**** Population: 1904 patients with bisphosphonate-naive mCRPC
**** Randomized to denosumab vs. zoledronate
**** Primary outcome: skeletal related events
**** Results:
***** Denosumab showed an improved time-to-first skeletal-related event (20.7 vs. 17.1 months, P = .008) and a longer time to first-and-subsequent skeletal-related events (HR 0.82, P = .004) (Fizazi et al, 2011).
***** No difference in overall survival or PFS between study arms
*** '''Adverse effects:'''
**** '''Osteonecrosis of the jaw'''
***** '''Occurs in about 2-4% of patients'''
**** '''Hypocalcemia'''
***** '''Concomitant administration of oral calcium supplements (1000 mg/day) and vitamin D (800 units/day) is often recommended.'''
**** '''Fatigue'''
**** '''Nausea'''
**** '''Hypophosphatemia'''
*** '''Advantage of denosumab is that it does not require dose adjustment or monitoring for renal impairment'''
** '''Optimal duration of zoledronic acid and denosumab in CRPC and bone metastases is undefined.§'''
*** '''The risk of osteonecrosis of the jaw appears to be related to time on bone-targeted therapy, caution should be taken in using these agents > 2 years'''
*** Methods to reduce risk of osteonecrosis of the jaw (ONJ) for patients treated with bone-targeted therapies (3):
**** Encourage good oral hygiene
**** Baseline dental evaluation for high-risk individuals
**** Avoidance of invasive dental surgery during therapy
** Denosumab and zoledronic acid are not approved and not indicated for SRE prevention in the treatment of metastatic castration-sensitive prostate cancer or for bone metastases prevention
** Zoledronic acid and denosumab have been used in combination with all the agents presently in use for the treatment of mCRPC. To date, there have been no additional safety issues of concern that have been reported.§
* '''Palliative radiation'''
** '''Focal bone pain in patients with CRPC can be well controlled using external-beam localized radiation therapy.'''
** '''In general, it is also recommended that painful areas that are shown to be abnormal on bone scintigraphy should be evaluated with plain radiographs or CT imaging to exclude the presence of osteolytic lesions or pathologic fractures.'''
** '''Malignant spinal cord compression is an oncological emergency that requires immediate diagnosis, if suspected, with an MRI. Options for treatment are radiation with (3):'''§
**# '''Steroids'''
**# '''Debulking surgery'''
**# '''Vertebrectomy with stabilization'''

===== Sequential treatments in mCRPC =====
* '''The optimal sequence of available options remains unknown. In general, it is felt that changing therapeutic mechanism of action with each line of therapy is likely to lead to better and longer lasting response'''