Treatment of Castration Resistant Prostate Cancer

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Treating castration-resistant prostate cancer (CRPC):

Androgen-deprivation therapy (ADT), is one of the most effective systemic palliative treatments known for prostate cancer.  It is effective, but most all treated patients develop clinical evidence of treatment resistance.  Once treatment resistant, there is cancer progression despite castrate levels of serum testosterone.  Disease treatment in patients with (hormone-refractory) metastatic castration-resistant prostate cancer, mCRPC, requires the use of nonhormonal approaches that can effectively control the growth of the disease.  

Patient assessment considerations:

• Are metasteses present?
• Is this a clinical versus biochemical relapse? 
• Is there the presence of symptoms (e.g., pain)?
• The PSA kinetics (e.g., PSA doubling time, PSA velocity).
• Discontinuation of antiandrogens can result in short-term clinical responses expressed by decreases in PSA levels, symptomatic benefits, and, less frequently, objective improvements in soft tissue and bone metastasis in a small proportion of patients.
• It has been recommended that in patients treated with antiandrogens in combination with other forms of androgen deprivation (e.g., LH-RH agonists) the first step should involve the discontinuation of these agents and careful observation including serial monitoring of PSA levels for a period of 4 to 8 weeks before embarking on the next therapeutic maneuver.

The next step is to determine which treatment should be used first:  

• In view of the potential higher toxicity profile associated with cytotoxic chemotherapy, a sequential hormonal approach may be a reasonable alternative for those patients with relatively limited metastatic disease who remain asymptomatic at the time of disease progression (e.g., rising serum PSA value without other clinical manifestations).

Nonmetastatic castration-resistant disease

• Patients often begin androgen deprivation at the first sign of a rising PSA, before clinical and radiologic evidence of metastasis is present.
• This group of patients, termed the M0 (nonmetastatic) castrate-resistant subset, is now seen in increasing proportions in the clinic.
• There is no consensus on the most appropriate management for these patients, although the sequential endocrine approach is the most commonly employed therapeutic modality.

Metastatic castration-resistant disease

• Metastatic prostate cancer has an affinity to spread to the bone.
• Tumors in the bone may cause pain, compression, or pathologic fractures, known as skeletal related events (SRE's).   
• Extensive bone marrow replacement may cause impairment in hematologic function.
• Visceral site involvement is relatively uncommon in prostate cancer, even in patients with widespread disease.
• Because of the frequent involvement of vetebrae by metastatic prostate cancer, the incidence of cord compression is of particular concern.  
• Consider secondary hormonal manipulations before initiation of cytotoxic chemotherapy.

Cytotoxic Chemotherapy

• Docetaxel is the standard treatment for metastatic castration-resistant prostate cancer. 
• It prolongs progression-free and overall survival, ameliorates pain, and improves quality of life. 
• Toxicity of docetaxel includes myelosuppression, fatigue, edema, moderate to modest neurotoxicity, hyperlacrimation, and changes in liver function.
• No other chemotherapy regimen has shown a survival advantage in CRPC, but mitoxantrone has been approved to palliate symptoms associated with metastatic disease.
• Cabazitaxel is a treatment option for patients with metastatic CRPC who have experienced progressive disease during or after docetaxel treatment.

The Neuroendocrine/Anaplastic Subtype

• Alterations in the differentiation pathway of prostate cancer can be seen in a small proportion of patients with advanced disease
• The laboratory and clinical evidence demonstrate these alterations.
• Despite high initial response rates with chemotherapy and radiation treatment, the prognosis of these patients remains poor and is dependent on various factors, including extent and location of metastases.
• PSA is most commonly undetectable (or levels are low/declining) despite evidence of rapid disease progression. 
• These tumors are invariably unresponsive to hormonal manipulations but highly sensitive to radiation therapy and platinum-etoposide combinations.

Pain and Epidural Cord Compression

• The goal is to maintain quality of life while managing the symptoms of the progressing cancer.  
• Radiation therapy is often the main modality of definitive treatment.
• Recent evidence suggests that surgery followed by radiation therapy may be beneficial in some patients.
• The overall prognosis of the underlying disease should be taken into consideration during treatment selection.

Bisphosphonates

• Bisphosphonates have become an integral part of the management of metastatic prostate cancer to the bones.
• Zoledronate and pamidronate have also been shown to increase mineral bone density in patients with nonmetastatic prostate cancer receiving long-term androgen deprivation. 
• Zoledronate is indicated for the treatment of patients with progressive prostate cancer with evidence of bone metastasis, and it is administered at a dose of 4 mg intravenously repeated at intervals of 3 to 4 weeks for several months. 
• Side effects include fatigue, myalgias, fever, anemia, and mild elevation of the serum creatinine concentration. 
• Hypocalcemia has been described, and concomitant use of oral calcium supplements (1500 mg/day) and vitamin D (400 units/day) is often recommended. 
• An unusual complication of zoledronate is the development of severe jaw pain associated with osteonecrosis of the mandibular bone. 
• This is most frequently seen in patients undergoing dental work or those with a history of poor dentition and chronic dental disease. Zoledronate should not be administered to patients with these problems.

Rank Ligand Inhibitors

• Inhibition of the RANKL system represents an evolving bone-targeted strategy.
• Denosumab, a fully human monoclonal antibody against RANKL has been approved for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
• Common toxicities of denosumab include fatigue, nausea, hypophosphatemia, hypocalcemia (5% grade ≥3), and osteonecrosis of the jaw (2%), and prophylactic calcium and vitamin D supplementation is strongly encouraged. 
• Denosumab (XGEVA) is an alternative to zoledronate for the prevention of skeletal-related events in patients with metastatic CRPC. 
• Denosumab does not require dose adjustment or monitoring for renal impairment. 
• The recommended dose of denosumab is 120 mg given by subcutaneous injection every 4 weeks.

Targeted Therapies-Angiogenesis Targets for treating mCRPC

• The FDA approved abiraterone acetate (ZYTIGA, Janssen Biotech, Horsham, PA) in April 2010 for the treatment of patients with mCRPC who have received prior docetaxel chemotherapy. This is one of the most important advancements in the treatment of prostate cancer.  

• The recommended dose of ZYTIGA is 1,000 mg administered orally once daily in
  combination with prednisone 5 mg administered orally twice daily. ZYTIGA must be taken
  on an empty stomach. No food should be consumed for at least two hours before the dose of
  ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. 
  The tablets should be swallowed whole with water.

  ZYTIGA in combination with prednisone is indicated for the treatment of patients with
  metastatic castration-resistant prostate cancer who have received prior
  chemotherapy containing docetaxel.

• A second randomized phase III trial (COU-AA-302) targeting men with docetaxel- and ketoconazole-naïve CRPC has recently been unblinded before completion due to positive results at the recommendation of the independent data monitring committee.    
• Results of the COU-AA-302 study were presented at ASCO 2012.   http://www.urotoday.com/Treatment-of-mCRCP/asco-2012-an-interview-with-charles-j-ryan-md-presentation-of-the-new-paradigms-for-hormone-therapy-in-prostate-cancer-clinical-symposium-at-the-asco-2012-annual-meeting.html
• Considering the efficacy and safety of abiraterone acetate in prostate cancer patients prior to chemotherapy, it is expected that abiraterone will be used clinically in both the predocetaxel and postdocetaxel settings.

Targeted Therapies-Androgen Receptor Modulation

• Enzalutamide (formerly MDV3100) is an investigational therapy in Phase 3 clinical development.
• Enzalutamide is the first oral androgen receptor signaling inhibitor (ARSI) in development for the treatment of early-stage and advanced prostate cancer.
• Enzalutamide (formerly MDV3100) is a potent oral nonsteroidal AR antagonist, in development (4/2012). 
• Enzalutamide has a novel mechanism of action. Enzalutamide has been shown in preclinical studies to provide a more complete suppression of the androgen receptor pathway. Enzalutamide slows growth and induces cell death in bicalutamide-resistant cancers via three complementary actions – enzalutamide competitively inhibits androgen (testosterone and dihydrotestosterone) binding to the androgen receptor, inhibits movement of the androgen receptor to the nucleus of prostate cancer cells (nuclear translocation), and inhibits binding to DNA. Enzalutamide inhibits proliferation and induces cancer cell death and tumor regression in animal models of advanced prostate cancer.
• Enzalutamide (formerly MDV3100) remains a potent antagonist of the AR in the castration-resistant state, even in the setting of overexpressed or constitutively activated AR. 
• Unlike other antiandrogens enzalutamide does not exhibit any measurable agonistic activity and is able to prevent AR nuclear translocation with resultant tumoricidal (not cytostatic) activity.
• Interim results from an open-label, U.S., Phase 1-2 study, showed that enzalutamide was associated with anti-tumor activity in patients who had become resistant to bicalutamide or other standard anti-androgen treatments, including both patients who had failed prior chemotherapy and patients who were chemotherapy naïve. 

Immunotherapy

Sipuleucel-T

• The sipuleucel-T (Provenge) autologous prostatic acid phosphatase (PAP)-loaded dendritic cell vaccine, is approved for use in the USA.
• Sipuleucel-T, studies found no difference in progression-free survival or PSA/radiographic response rates. 
• Some investigators attribute the discordance between progression-free and overall survival to a possible class effect of immunotherapy agents.

CTLA-4 Inhibition

• Clinical trials using the monoclonal anti-CTLA-4 antibody, ipilimumab, are ongoing in men with metastatic CRPC.
• There are eight clinical studies with ipilimumab in prostate cancer according to ClinicalTrials.gov, including five that are currently active or recruiting.
• Bristol-Myers announced that the ‘024 study [ClinicalTrials.gov identifier NCT00324155] met its primary endpoint of overall survival.
• The ‘024 study is in patients with untreated Stage III [unresectable] or IV melanoma receiving dacarbazine plus 10 mg/kg ipilimumab versus dacarbazine with placebo.

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