SUMMARY: Abiraterone acetate (ZYTIGA®) is a novel, targeted, oral androgen biosynthesis inhibitor that decreases androgen production in the adrenal glands, testes and prostate cancer cells by inhibiting a steroidal enzyme CYP17. This agent, was approved by the FDA in April, 2011 for use in combination with prednisone, for the treatment of patients with metastatic CRPC (Castrate Resistant Prostate Cancer), who have received prior chemotherapy containing docetaxel (TAXOTERE®). Patients with high risk localized prostate cancer do poorly in spite of aggressive local therapies. To improve outcomes in this patient population, the authors conducted a neoadjuvant trial in which patients with localized prostate cancer with high risk features were divided into two groups. The first group (n = 28) was treated with the LHRH analog, LUPRON® (Leuprolide acetate) for 12 weeks, followed by 12 weeks of combination treatment with LUPRON® and ZYTIGA® . The second group (n = 30) received neoadjuvant LUPRON® plus ZYTIGA® for the entire 24 week period. Patients had radical prostatectomies following their neoadjuvant therapy. Fifty eight patients were enrolled and the eligibility criteria included either T3 disease, a Gleason score of ≥7, a prostate-specific antigen (PSA) level ≥20, or a PSA velocity >2 ng/mL/year. Post prostatectomy specimen analysis revealed that patients treated with the combination of LUPRON® plus ZYTIGA® for the entire 24 week period has a complete pathologic response (pCR) or near complete pCR (≤ 5mm residual tumor) rate amounting to 34%. This benefit was seen without significant systemic toxicities. The authors concluded that neoadjuvant androgen deprivation therapy may significantly improve outcomes in high risk patients with localized disease and will need to be studied further. Taplin ME, Montgomery RB, Logothetis C, et al. J Clin Oncol 30, 2012 (suppl; abstr 4521)
Tag: Prostate Cancer
Effect of MDV3100, an androgen receptor signaling inhibitor (ARSI), on overall survival in patients with prostate cancer post docetaxel Results from the phase III AFFIRM study
SUMMARY: MDV3100 is an androgen receptor antagonist with a significantly higher binding affinity for the androgen receptor (AR) compared to the antiandrogen bicalutamide and there by competitively inhibits the binding of androgens to the androgen receptor. Majority of the patients with advanced prostate cancer become refractory to hormone therapy because of increased production of androgen receptors by the tumors as well as mutated androgen receptors. The superiority of this novel agent, MDV3100, is based on the fact that the expression of androgen dependent genes are downregulated with MDV 3100 leading to cell death or apoptosis, whereas with bicalutamide the expression of these genes are upregulated. Further MDV3100 continues to antagonize mutated androgen receptors on the prostate tumor cells in contrast to bicalutamide which behaves as an agonist. It is thus an androgen receptor signaling inhibitor (ARSI). The AFFIRM clinical trial is a randomized, multinational phase III study in which patients who had received prior docetaxel-based chemotherapy regimens were randomized 2:1 to receive either MDV3100, 160 mg/day or placebo. Patients treated with MDV3100 had a median survival of 18.4 months, compared with 13.6 months for men treated with placebo, with a median OS advantage of 4.8 months and a reduction in the risk of death by 37%. Scher HI, Fizazi K, Saad F, et al. J Clin Oncol 30, 2012 (suppl 5; abstr LBA1)
ABIRATERONE ACETATE (AA) PLUS LOW DOSE PREDNISONE (P) IMPROVES OVERALL SURVIVAL (OS) IN PATIENTS (PTS) WITH METASTATIC CASTRATIONRESISTANT PROSTATE CANCER (MCRPC) WHO HAVE PROGRESSED AFTER DOCETAXEL-BASED CHEMOTHERAPY (CHEMO) RESULTS OF COU-AA-301, A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE III STUDY
SUMMARY: Abiraterone acetate (ZYTIGA®) is a novel, targeted, oral androgen biosynthesis inhibitor that decreases androgen production in the adrenal glands, testes and prostate cancer cells by inhibiting a steroidal enzyme CYP17. This agent was approved by the FDA in April, 2011 for use in combination with prednisone for the treatment of patients with metastatic CRPC (Castrate Resistant Prostate Cancer), who have received prior chemotherapy containing docetaxel (TAXOTERE®). This approval was based on a randomized, placebo controlled phase III trial which included 1195 patients with metastatic CRPC, previously treated with one or two chemotherapy regimens, at least one of which contained TAXOTERE®. Patients were randomly assigned (2:1) to receive either ZYTIGA® plus low-dose prednisone (N=797) or placebo plus low dose prednisone (N=398). Treatment was continued until disease progression. The primary endpoint was overall survival. Results from a pre-specified interim analysis demonstrated that patients treated with ZYTIGA® plus low-dose prednisone showed a statistically significant improvement in overall survival as well secondary endpoints such as, time to PSA progression and radiographic progression-free survival. Treatment with ZYTIGA® resulted in a 35 percent reduction in the risk of death and a 36 percent increase in median survival compared with placebo. The most common adverse events were edema, hypertension, joint discomfort, diarrhea, hypokalemia, and hypophosphatemia. This novel therapeutic agent is a major and important medical advance in the management of patients with metastatic CRPC. With the availability of several new agents for the treatment of CRPC, it may be important to properly sequence these available drugs to get the best of each treatment intervention and thus improve overall survival. Annals of Oncology 21 (Supplement 8): viii1-viii12. 2010. Ref Type: Abstract
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment a randomised open-label trial
SUMMARY: The TROPIC trial (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated With a docetaxel (TAXOTERE®)- Containing Regimen) involved 755 men in 26 countries with metastatic prostate cancer who were castration resistant. Patients were randomized to receive either Cabazitaxel (JEVTANA®) 25 mg/m2 or Mitoxantrone 12 mg/m2 three times a week and both groups received prednisone 10 mg daily through out the course of their treatment. The combination of JEVTANA® and prednisone resulted in median overall survival of 15.1 months compared to 12.7 months for the Mitoxantrone group. There was a 30% reduction in the risk of death for the JEVTANA® group. This led to the approval of JEVTANA® for the treatment of hormone-refractory metastatic prostate cancer, previously treated with a TAXOTERE® containing regimen. Lancet 2010;376:1147-1154
Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer
SUMMARY: Sipuleucel-T (PROVENGE®) is a therapeutic cancer vaccine developed to boost the patients immune system to fight prostate cancer. In a double blind randomized phase III trial, 512 patients with metastatic castrate-resistant prostate cancer received PROVENGE® vaccine (341) or a placebo (171). There was a 4.1 month improvement in median survival for patients receiving the vaccine compared to those receiving a placebo (25.8 versus 21.7 months) and a 22% reduction in the risk of death in the vaccine group. Because of the slow onset of action of any vaccine therapy, this option may be appropriate for individuals with less aggressive disease. N Engl J Med 2010;363:411-422
Oncoprescribe Blog Prostate Cancer – Androgen Independent or Castrate Resistant
It is not semantics anymore. Prostate Cancer is a heterogeneous disease. It appears that in patients touted to have Hormone Refractory Prostate Cancer (HRPC), the cells continue to produce androgen receptor message even in the absence of androgens. The tumor cells are therefore not androgen independent. On the contrary, they continue to thrive, having access to androgens or androgen precursors, by various different mechanisms. It is for this reason imperative that one continue chemical castration with LHRH agonists concurrently with other lines of treatment including chemotherapy.
So the appropriate term should be Castrate Resistant Prostate Cancer rather than Androgen Independent Prostate Cancer.
Oncoprescribe Blog Personalized medicine for prostate cancer patients
Prolaris is a molecular diagnostic tool developed by Myriad Genetics, Inc. This 46 gene panel is capable of predicting aggressiveness of prostate cancer and can be used in conjunction with Gleason score and PSA. By measuring the expression level of genes involved with cell cycle progression, this test is able to differentiate indolent from aggressive prostate cancers and therefore predict disease outcome.
In a retrospective analysis of 366 patients who had undergone radical prostatectomy and 337 patients with clinically localized prostate cancer, this gene panel was able to give a favorable and unfavorable score to patient subsets and thus predict clinical outcomes. This prognostic information will allow clinicians to recommend appropriate therapy at the time of diagnosis of prostate cancer.
So we have gene signature assays for breast cancer, colon cancer, lung cancer (oncoprescribe blog) and now for prostate cancer as well. In the end, patients benefit.
Oncoprescribe Blog Abiraterone – another promising agent in CRPC
Abiraterone is a steroidal agent and inhibits CYP17A, an enzyme necessary for the production of androgen precursors and subsequently testosterone. It is capable of inhibiting testosterone production both in the adrenals as well as the testes.
Data from a recent phase III trial was presented at the ESMO meeting and in this International trial involving 1,195 patients, Abiraterone plus a steroid was compared with placebo plus steroid in patients with CRPC (Castrate-Resistant Prostate Cancer) who had failed chemotherapy with Docetaxel. Following an interim analysis and upon recommendation from the Independent Data Monitoring Committeee, the study had to be unblinded, as there was a significant improvement in overall survival in the group receiving Abiraterone. With the availability of several new agents for the treatment of CRPC, it may be important to properly sequence these available drugs to get the best of each treatment intervention and thus improve long term survival with limited toxicity.
Oncoprescribe Blog Cabazitaxel – Another new agent for CRPC
Cabazitaxel is a microtubule inhibitor approved for the treatment of patients with CRPC (Castrate-Resistant Prostate Cancer) who have progressed on Docetaxel. This agent in a randomized phase III trial (TROPIC) demonstrated a significant improvement in Overall Survival (OS) compared with Mitoxantrone, with a 30% reduction in the risk of death. We now have another option for the treatment of CRPC which until not too long back was considered as a disease for which chemotherapy was not effective.
Oncoprescribe Blog CRPC – A wave of new agents, but first Sipuleucel-T
This year 2 new agents have been approved for the treatment of Castrate-Resistant Prostate Cancer – Sipuleucel-T and Cabazitaxel. Sipuleucel-T is composed of autologous antigen-presenting cells (APC’s) from the patient, cultured with a fusion protein PA2024 (Prostate Acid Phosphatase-PAP linked to granulocyte/macrophage colony-stimulating factor). Prostatic Acid Phosphatase (PAP) is an antigen expressed in most prostate cancers. When administered, Sipuleucel-T an autologous active cellular immunotherapy stimulates T cell immunity against PAP and thus the prostate cancer cells. This agent demonstrated improvement in median survival and is best suited for those patients who are asymptomatic or have minimal symptoms with CRPC. It is important to note that this agent is given as three infusions 2 weeks apart and one may not see a drop in the PSA or improvement in the bone scan findings until after three months following treatment. For this reason it is best to consider this agent well before chemotherapy with docetaxel is planned. The number of patients who can be treated with this agent presently is limited due to various barriers associated with the processing of autologous Antigen Presenting Cells. It is important to realize that steroids may counter the T cell response associated with this agent and therefore should be avoided.