The major biologic processes under therapeutic investigation in prostate cancer involve growth and survival, chemotherapy and hormone therapy resistance, extragonadal androgen production, modulation of the androgen receptor, angiogenesis, the bone interface, epigenetic regulation, immune surveillance and escape, and stem cell renewal.
Tumor angiogenesis is likely to be an important biologic component of prostate cancer metastasis, and elevated levels of the potent angiogenic molecule vascular endothelial growth factor (VEGF) have been shown to correlate with advanced clinical stage and survival.
Patient assessment considerations:
Are metastases 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.
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 vertebrae by metastatic prostate cancer, the incidence of cord compression is of particular concern.
Consider secondary hormonal manipulations before initiation of cytotoxic chemotherapy.
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.
Targeted Therapies-Angiogenesis Targets
The FDA approved abiraterone acetate (Zytiga, Janssen Biotech, Horsham, PA) in April 2010 for the treatment of patients with metastatic CRPC 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 mCRPC who have received prior chemotherapy containing docetaxel.
There is new evidence presented at ASCO 2012 (June) from a second randomized phase III trial (COU-AA-302) targeting men with docetaxel- and ketoconazole-naïve CRPC has positive results. This trial was recently unblinded before completion at the recommendation of the Independent Data Monitoring Committee and the study sponsor.
This Phase III trial utilized co-primary endpoints, which were utilized for the reason that many of these patients have a fairly long expected survival. Therefore, only measuring overall survival as an endpoint of the trial can be complicated or contaminated by many other treatments that these patients could receive.
In light of that Radiographic Progression Free Survival (rPFS) was used along with overall survival (OS) as co-primary endpoints.
The results of the study show that patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate plus prednisone, when compared to prednisone alone, led to a statistically significant and clinically meaningful delay in disease progression. By clinically meaningful, it more than doubled the time until patient disease progressed compared for the patients in the abiraterone acetate plus prednisone arm to those receiving prednisone alone.
For the purposes of this study, a rising PSA did not constitute progression of the disease. What constituted disease progression was the development of new metastatic lesions. And it is important to note that in this study the average PSA was 45 and about 50% of the patients had >10 bone metastases at study enrollment.
This is the first randomized study to demonstrate a radiographic progression-free survival benefit and a strong trend for overall survival in this patient population.
In addition to looking at rPFS and overall survival, we looked at a series of other clinically relevant endpoints:
Median time to opiate use for cancer pain: the median time in the abiraterone acetate plus prednisone arm was not reached and was 23.7 months in the control arm (HR=0.69; 95% CI: [0.57, 0.83]; p=0.0001).
Median time to initiation of cytotoxic chemotherapy for prostate cancer: 25.2 months for the abiraterone acetate plus prednisone arm vs. 16.8 months for the control arm (HR=0.58 [95% CI: 0.49, 0.69]; p<0.0001).
Median time to decline in performance status: 12.3 months for the abiraterone acetate plus prednisone arm vs. 10.9 months for the control arm (HR=0.82; 95% CI: [0.71, 0.94]; p=0.0053) for an increase in the Eastern Cooperative Oncology Group (ECOG) performance score of one point or more. The ECOG performance score is a standard measure used to assess functional status of a patient and is often used to determine prognosis and appropriate treatment.
Median time to PSA progression: 11.1 months for the abiraterone acetate plus prednisone arm vs. 5.6 months for the control arm (HR=0.49; 95% CI: [0.42, 0.57], p<0.0001), based on The Prostate Cancer Clinical Trials Working Group (PCWG2) criteria.
On every one of these secondary endpoints, patients receiving abiraterone acetate plus prednisone had a statistically significant prolongation on average until that event occurred.
So, in summary these results show that patients:
can live longer without disease progression
can live longer without symptoms
can live longer until performance status deteriorates
and live longer until receiving chemotherapy
and probably live longer overall.
The overall survival results of this trial are continuing to mature. And at the time of this interim analysis, a strong trend in favor of abiraterone acetate plus prednisone arm compared to the prednisone arm, (p=0.0097).
This is an important study with all clinically relevant endpoints favoring treatment with abiraterone acetate plus prednisone, and is also the first to suggest that inhibiting androgen production significantly delays initiation of chemotherapy.
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.
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.
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.
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