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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 advanced 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 metastatic castration-resistant prostate cancer, mCRPC requires the use of approaches that can effectively control the growth of the disease.  

Patient assessment considerations:

  • Are metastases present? in the bone?  in visceral tissue?
  • 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.

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.

Immunotherapy - Sipuleucel-T

Sipuleucel-T is an autologous cellular immunotherapy that is approved in the United States and the European Union for the treatment of patients with asymptomatic or minimally symptomatic metastatic CRPC.
The patient’s peripheral blood mononuclear cells are harvested and treated outside the body with the fusion product of prostatic acid phosphatase and granulocyte-macrophage colony stimulating factor. Patients receive a total of 3 sipuleucel-T infusions at weeks 0, 2, and 4.
The procedure was approved following the phase 3 IMPACT (Immunotherapy Prostate Adenocarcinoma Treatment) trial
of 512 patients, which demonstrated a 22% reduction in the risk of death relative to placebo.

The results from an exploratory analyses from the IMPACT trial suggest that the greatest magnitude of benefit with sipuleucel-T treatment was observed among patients with better baseline prognostic factors and particularly those with lower baseline PSA values. These findings provide a rationale for immunotherapy as an early step in sequencing treatment algorithms for mCRPC and also suggest a greater benefit when immunotherapy is used earlier in the treatment paradigm.

Sipuleucel-T efficacy is predicated on the ability to stimulate the patient’s antigen-presenting cells (APCs) to recognize the prostatic acid phosphatase tumor antigen, which is present in 95% of prostate tumors.

The therapy’s resulting tumor cell lysis may lead to the release of secondary tumor antigens that effect a broader immune response, a phenomenon known as antigen spread.

In the IMPACT trial, patients treated with sipuleucel-T produced consistent immunoglobulin G (IgG) responses against secondary antigens 3 to 4 months after treatment. In contrast, no IgG responses against secondary antigens were observed in the control arm. An analysis of patient serum collected during the IMPACT trial aimed to assess the immune response against secondary tumor antigens and determine the relationship between secondary immune response and clinical outcome.
The study analyzed serum taken at baseline, 6 weeks, 14 weeks, and 26 weeks after treatment initiation. IgG response was defined as a minimum 2-fold increase in the antigen-specific level relative to baseline by testing on protein microarrays. The relationship between IgG response and OS was assessed using a Cox regression model adjusted for prior bisphosphonate use and baseline prognostic factors, such as levels of serum PSA and lactate dehydrogenase, the presence or absence of bone lesions, and Gleason score. IgG responses to 244 secondary antigens were assessed in serum samples taken from 93 patients in the sipuleucel-T arm and 40 patients in the control arm. From these 244 antigens, 10 candidate secondary antigens in 2 categories were selected for confirmation. Antigens that elicited a response at week 14 and had a known relevancy to cancer development included KRAS, ERAS, KLK2, LGALS8, and TSPAN13. Antigens that showed the highest average increase at week 14 in the sipuleucel-T arm relative to baseline, regardless of relevance to cancer development, included LGALS3, ECE1, ANPEP, CACNG1, and FBXO6. 

Seven of these candidate genes were confirmed using a bead-based suspension array assay that showed a significant increase in IgG response at week 14 (P<.01). The outcomes were validated by analyzing patient serum samples from the ProACT (Prostate Advanced Cancer Treatment) trial that showed a significant increase in IgG response from baseline to 4 months after treatment

An IgG response at week 14 to either the primary antigen (prostatic acid phosphatase) or any of the 7 antigens alone was not significantly associated with OS. However, IgG responses to prostatic acid phosphatase as well as 2 or more secondary antigens were associated with improved OS (P<.01; HR, <0.4;). The authors concluded that the new methodology could facilitate the identification of serum biomarkers as a surrogate for assessing in vivo therapeutic effects in patients with prostate cancer or other malignancies.

Abiraterone Acetate  (Zytiga®)

ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

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. 

In the COU-301 trial, Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy.

The COU-302 trial evaluated Abiraterone acetate in patients who had not received previous chemotherapy.  In this study involving men with metastatic castration-resistant prostate cancer, abiraterone plus low-dose prednisone resulted in prolonged radiographic progression-free survival (median time to event, 16.5 months vs. 8.3 months; hazard ratio, 0.53), as compared with placebo plus prednisone.

Patients receiving abiraterone also had an extended time until the initiation of opiate analgesia, treatment with cytotoxic chemotherapy, or a decline in performance status, as well as delays in PSA progression, onset of pain, and decline in health-related quality of life.  

The durable antitumor effect and safety profile of abiraterone confirms earlier experience that it can be used long term without concern for life-threatening toxic effects.

In addition to the marked improvement in radiographic progression-free survival, treatment with abiraterone was associated with a trend toward improved overall survival. Evidence of the magnitude of the survival benefit of abiraterone–prednisone, as compared with prednisone alone, was that treatment effects were consistently favorable across all prespecified patient subgroups, including older men and those with a decreased performance status, increased pain, and increased disease burden.

The use of abiraterone after crossover among patients originally assigned to the prednisone-alone group may affect the ability to show statistical significance in subsequent analyses of overall survival. Despite the high disease burden and the proportion of patients with high-grade tumors (Gleason score, ≥8) who were enrolled, the survival curves did not separate until after approximately 12 months. This finding can be ascribed to the use of an active prednisone control and the low rate of early death in asymptomatic or mildly symptomatic patients with metastatic castration-resistant cancer.

In addition, a strong trend toward improved survival (hazard ratio, 0.75) was evident at the time at which 43% of the prespecified total number of events required for the final analysis had occurred. This consistent pattern of benefit resulted in the unanimous decision of the data and safety monitoring committee to recommend unblinding of the study and crossover of patients in the prednisone-alone group to abiraterone treatment.

The safety of abiraterone in this study was similar to that previously reported in men with metastatic castration-resistant prostate cancer and disease progression after docetaxel chemotherapy.19 No toxic effects unique to this patient population were identified (a finding that was consistent with previous studies), despite a longer duration of abiraterone–prednisone treatment.

In summary, the results show benefit from the use of abiraterone in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer who have not received previous chemotherapy. These findings include increased rates of radiographic progression-free survival and overall survival, as well as clinically meaningful secondary end points, such as delays in the use of opiates for pain and chemotherapy and patient-reported outcomes related to health-related quality of life.

Despite the various therapies available for men with metastatic castration-resistant prostate cancer, a need remains for effective nontoxic agents that can improve and maintain the quality and duration of life while preventing the morbidity associated with disease progression.

 Enzalutamide

Enzalutamide is an androgen receptor agonist indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.

Enzalutamide is the first oral androgen receptor signaling inhibitor (ARSI) in development for the treatment of early-stage and advanced prostate cancer.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.

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.
  • 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).

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