Tags

abiraterone acetate

  • Phase 1b Study of Abiraterone Acetate Plus Prednisone and Docetaxel in Patients with Metastatic Castration-resistant Prostate Cancer.

    Coadministration of docetaxel and abiraterone acetate plus prednisone (AA + P) may benefit patients with metastatic castration-resistant prostate cancer (mCRPC) because of complementary mechanisms of action.

    Published February 25, 2016
  • Platelet-lymphocyte and neutrophil-lymphocyte ratios are prognostic but not predictive of response to abiraterone acetate in metastatic castration-resistant prostate cancer.

    Recently neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have been reported to be inflammatory parameters that confer poorer outcome in metastatic castration-resistant prostate cancer (mCPRPC).

    Published July 28, 2017
  • Podcast: Castration-resistant prostate cancer: AUA Guideline 2013 commentary, by E. David Crawford, MD

    BERKELEY, CA USA (UroToday.com) - Over the past few years, a number of new and promising treatments have emerged to improve survival in patients whose prostate cancer is not responsive to traditional androgen deprivation therapy (ADT).

    Published May 30, 2013
  • Post-docetaxel therapy in castration resistant prostate cancer - the forest is growing in the desert, "Beyond the Abstract," by Amelia Altavilla, MD and Roberto Iacovelli, MD

    BERKELEY, CA (UroToday.com) - The current landscape of treatment of castration-resistant prostate cancer (CRPC) has recently changed. Until 2004, docetaxel[1] and androgen-deprivation therapy[2] were the only treatments able to improve overall survival (OS).

    Published January 2, 2013
  • Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: a retrospective cohort study.

    We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers.

    Published June 6, 2016
  • Prescribing Patterns of Oral Antineoplastic Therapies Observed in the Treatment of Patients With Advanced Prostate Cancer Between 2012 and 2014: Results of an Oncology EMR Analysis.

    The purpose of this study was to examine, using a US electronic medical records (EMR) database, the clinical characteristics and real-world treatment sequences in men with advanced prostate cancer who initiated treatment with abiraterone acetate or enzalutamide.

    Published August 10, 2016
  • Prior Endocrine Therapy Impact on Abiraterone Acetate Clinical Efficacy in Metastatic Castration-resistant Prostate Cancer: Post-hoc Analysis of Randomised Phase 3 Studies.

    The duration of prior hormonal treatment can predict responses to subsequent therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).

    To determine if prior endocrine therapy duration is an indicator of abiraterone acetate (AA) sensitivity.

    Published November 3, 2015
  • Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer.

    The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an intermediate endpoint for overall survival (OS).

    Published March 13, 2016
  • Repeated measures analysis of patient-reported outcomes in prostate cancer after abiraterone acetate.

    Metastatic castration-resistant prostate cancer (mCRPC) is typically associated with declining health-related quality of life (HR-QoL).

    To assess patient experience with abiraterone acetate (hereafter abiraterone) plus prednisone longitudinally.

    Published May 10, 2016
  • Safety and efficacy of abiraterone acetate in chemotherapy-naive patients with metastatic castration-resistant prostate cancer: an Italian multicenter "real life" study.

    To evaluate the safety and efficacy of abiraterone acetate (AA) in the "real life" clinical practice for men with chemotherapy-naïve metastatic castration-resistant prostate.

    A consecutive series of patients with mCRPC in 9 Italian tertiary centres treated with AA was collected.

    Published November 14, 2017
  • Safety and outcomes of new generation hormone-therapy in elderly chemotherapy-naive metastatic castration-resistant prostate cancer patients in the real world.

    Abiraterone acetate and enzalutamide are standard treatments for chemotherapy-naive metastatic castration-resistant prostate cancer (CN-mCRPC). The purpose of this study was to evaluate the effectiveness and safety of these medications in elderly (≥ 75 years old) compared with young CN-mCRPC patients in a real-world clinical setting.

    Published March 20, 2019
  • Safety of long-term exposure to abiraterone acetate in patients with castration-resistant prostate cancer and concomitant cardiovascular risk factors.

    We aimed to evaluate the long-term safety profile of abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) with controlled cardiovascular comorbidities or risk factors.

    Published September 8, 2016
  • Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: A network meta-analysis.

    Androgen deprivation therapy (ADT) has long been the gold standard for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Clinical trials have demonstrated significant survival benefits when docetaxel (DOC) or abiraterone acetate (AA) and prednisone (P) are added to ADT, necessitating comparison of these combination treatments.

    Published September 21, 2018
  • Systemic immune-inflammation index predicts the combined clinical outcome after sequential therapy with abiraterone and docetaxel for metastatic castration-resistant prostate cancer patients.

    To compare the antitumor effect of abiraterone (AA) followed by docetaxel-prednisone (DP) or vice versa in metastatic castration-resistant prostate cancer (mCRPC) patients, and explored factors that might predict combined PSA-PFS, combined rPFS and OS.

    Published January 4, 2018
  • The impact of statin use on the efficacy of abiraterone acetate in patients with castration-resistant prostate cancer.

    Statins compete with DHEAS for influx through the SLCO2B1 transporter, which may prolong time to progression (TTP) on androgen deprivation therapy. Abiraterone acetate (AA) may also undergo SLCO-mediated transport.

    Published August 9, 2017
  • The incidence and relative risk of cardiovascular toxicity in patients treated with new hormonal agents for castration-resistant prostate cancer.

    New hormonal agents are available for treating metastatic castration-resistant prostate cancer (mCRPC). We aim to define the incidence and relative risk (RR) of cardiovascular events in mCRPC patients treated with these agents.

    Published July 15, 2015
  • The optimal treatment of metastatic hormone-naive prostate cancer: abiraterone acetate or docetaxel?

    To determine whether abiraterone acetate or docetaxel should be regarded as the current standard of care for metastatic hormone-naive prostate cancer (mHNPC).

    A network meta-analysis (NMA) using the frequentist approach and generalized pairwise modeling was computed.

    Published December 6, 2017
  • The Phase 3 COU-AA-302 Study of Abiraterone Acetate Plus Prednisone in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Stratified Analysis Based on Pain, Prostate-specific Antigen, and Gleason Score.

    In the COU-AA-302 study (NCT00887198), abiraterone acetate plus prednisone (AAP) significantly improved outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) versus prednisone alone.

    Published September 26, 2017
  • The role of bisphosphonates or denosumab in light of the availability of new therapies for prostate cancer.

    Most men with advanced prostate cancer will develop bone metastases, which have a substantial impact on quality of life. Bone metastases can lead to skeletal-related events (SREs), which place a burden on patients and healthcare systems.

    Published May 31, 2018
  • The third line of treatment for metastatic prostate cancer patients: Option or strategy?

    New agents for metastatic castration-resistant prostate cancer (CRPC) developed in the past 3 years include cabaziataxel (Cbz), abiraterone acetate (AA) and enzalutamide (E).

    Published July 28, 2015
  • Treatment of Castration Resistant Prostate Cancer

    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).

    References:

    • Attard G, Reid AH, Yap TA, et al: Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol  2008; 26:4563-4571.
    • Beer TM: Advances in systemic therapy for prostate cancer: chemotherapy for androgen-independent prostate cancer. Proc Am Soc Clin Oncol  2004; 23:225-232.
    • Berry S, Waldron T, Winquist E, et al: The use of bisphosphonates in men with hormone-refractory prostate cancer: a systematic review of randomized trials. Can J Urol  2006; 13:3180-3188.
    • Carducci MA, Nelson JB, Bowling K, et al: Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics. J Clin Oncol  2002; 20:2171-2180.
    • Carducci MA, Saad F, Abrahamsson PA, et al: A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer  2007; 110:1959-1966.
    • Chen Y, Clegg NJ, Scher HI: Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol  2009; 10:981-991.
    • Crawford E, Eisenberger M, McLeod D, et al: A controlled randomized trial of leuprolide with and without flutamide in prostatic cancer. N Engl J Med  1989; 321:419-424.
    • D’Amico A, Moul J, Carroll PR, et al: Surrogate end point for prostate cancer specific mortality in patients with nonmetastatic hormone refractory prostate cancer. J Urol  2005; 173:1572-1576.
    • de Bono JS, Oudard S, Ozguroglu M, et al: Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet  2010; 376:1147-1154.
    • de Bono JS, Logothetis CJ, Molina A, et al: Improved survival from metastatic prostate cancer with abiraterone acetate. N Engl J Med  2011; 364:1995-2005.
    • Dotan ZA, Bianco FJ, Rabbani F, et al: Pattern of PSA failure dictates the probability of a positive bone scan in patients with increasing serum PSAs after radical prostatectomy. J Clin Oncol  2005; 23:1962-1968.
    • Drake CG, Fan LQ, Thakurta DG, et al. Antigen spread and survival with sipuleucel-T in patients with advanced prostate cancer [ASCO GU abstract 88]. J Clin Oncol. 2014;32(4)(suppl).
    • Efstathiou E, Titus M, Tsavachidou D, et al. Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone. J Clin Oncol 2012;30:637-643.
    • Feldman BJ, Feldman D: The development of androgen independent prostate cancer. Nat Rev Cancer  2001; 1:34-45.
    • Fizazi K, Carducci M, Smith M, et al: Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomized double-blind study. Lancet  2011; 377:813-822.
    • Fizazi K, Lipton A, Mariette X, et al: Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol  2009; 27:1564-1571.
    • Fong L, Kwek SS, O’Brien S, et al: Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res  2009; 69:609-615.
    • Gabriel K, Schiff D: Metastatic spinal cord compression by solid tumors. Semin Neurol  2004; 24:375-383.
    • Gardner TA, Petrylak DP, Corman JM, et al. Immune response with sipuleucel-T in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): phase II ProACT study [ASCO GU abstract 148]. J Clin Oncol. 2013;30(suppl 6).
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    • Hoos A, Eggermont AM, Janetzki S, et al: Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst  2010; 102:1388-1397.
    • Harzstark AL, Small EJ: Immunotherapeutics in development for prostate cancer. Oncologist  2009; 14:391-398.
    • Hoos A, Eggermont AM, Janetzki S, et al: Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst  2010; 102:1388-1397.
    • Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. 
    • Kantoff PW, Higano CS, Shore ND, et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med  2010; 363:411-422.
    • Nelson JB, Bagnato A, Battistini B, et al: The endothelin axis: emerging role in cancer. Nat Rev Cancer  2003; 3:110-116.
    • Olson BM, McNeel DG. Sipuleucel-T: immunotherapy for advanced prostate cancer. Open Access JUrol. 2011;3:49-60.
    • Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomized trial. Lancet  2005; 366:643-648.
    • Roodman GD: Mechanisms of bone metastasis. N Engl J Med  2004; 350:1655-1664.
    • Saad F, Gleason DM, Murray R, et al: Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst  2004; 96:879-882.
    • Sawyers CL, Tran C, Wongvipat J, et al: Characterization of a new anti-androgen MDV-3100 effective in preclinical models of hormone refractory prostate cancer. Genitourinary Cancer Symposium  2007.abstract 48
    • Scher HI, Eisenberger M, D’Amico AV, et al: Eligibility and outcomes reporting for clinical trials for patients in the state of a rising PSA: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol  2004; 22:537-556.
    • Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol  2008; 26:1148-1159.
    • Small EJ, Schellhammer PF, Higano CS, et al: Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol  2006; 24:3089-3094.
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    Published June 23, 2014
  • Treatment of mCRCP

    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.

     

    Insert content here

    Published July 12, 2012
  • Treatment of Metastatic, Castration-Resistant, Docetaxel-Resistant Prostate Cancer: A Systematic Review of Literature With a Network Meta-Analysis of Randomized Clinical Trials.

    To compare the efficacy of abiraterone acetate, enzalutamide, cabazitaxel and Radium-223 in the treatment of castration-resistant, docetaxel-resistant metastatic prostate cancer.

    An indirect comparison of overall survival (OS) and time to PSA progression among abiraterone acetate, enzalutamide, cabazitaxel and Radium-223 was performed with a network meta-analysis.

    Published April 9, 2018
  • Treatment Sequences and Pharmacy Costs of 2 New Therapies for Metastatic Castration-Resistant Prostate Cancer.

    The approval of new therapies for metastatic castration-resistant prostate cancer (mCRPC), including the oral agents abiraterone acetate and enzalutamide, has altered the standard of care for patients with mCRPC.

    Published August 25, 2015
  • Ureteral Metastasis: Uncommon Manifestation in Prostate Cancer.

    Ureteral metastasis from a primary prostate cancer is a rare event in the initial diagnosis and progression of prostate cancer. We report here the case of a 72- year-old patient who was treated for castration-resistant metastatic prostate cancer involving bone, intra-abdominal lymph nodes, bilateral adrenal glands, and a small distal ureteral lesion with left hydronephrosis considered in remission, with a luteinizing hormone-releasing hormone analog plus abiraterone acetate (AA) and prednisone after initial docetaxel plus prednisone chemotherapy.

    Published November 4, 2015
  • What do we know about treatment sequencing of abiraterone, enzalutamide, and chemotherapy in metastatic castration-resistant prostate cancer?

    To present a systematic review of the different therapeutic sequences in metastatic castration-resistant prostate cancer (mCRPC).

    Evidence acquisition on therapeutic sequences in mCRPC was performed by a MEDLINE search using combination of the following key words: "prostate cancer," "metastatic," "castration resistant," "enzalutamide," "abiraterone," "treatment sequencing," "cabazitaxel," "docetaxel.

    Published October 2, 2015

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