Cabazitaxel Articles

Articles

  • [Metastatic castration-resistant prostate cancer : Clinical data, new treatment options and therapy monitoring].

    Therapies currently available in Germany for metastatic castration-resistant prostate cancer (mCRPC) include docetaxel, cabazitaxel, abiraterone acetate, enzalutamide and radium-223, all of which offer a potential survival benefit that adds up in their sequential application to a significant overall survival benefit.

    Published July 21, 2016
  • [Metastatic castration-resistant prostate cancer : Use of cabazitaxel taking into consideration current data].

    At the 2016 ASCO annual meeting, new data from two randomized phase III studies concerning taxane-based chemotherapy as a treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC) were presented.

    Published November 1, 2017
  • [Metastatic prostate cancer : Update: position paper for the use of chemotherapy].

    Taxen-based chemotherapy has been established as an effective treatment option in castration-resistant metastatic prostate cancer (mCRPC). Randomized phase III studies, however, have shown that even in the hormone-naïve metastatic state, the early use of chemotherapy in addition to the classical androgen deprivation therapy (ADT) approach leads to a significant increase in median overall survival.

    Published July 18, 2017
  • #ASCO14 - Poster: Safety results of the enzalutamide expanded access program in the United States and Canada for patients with metastatic castration-resistant prostate cancer previously treated with docetaxel

    CHICAGO, IL USA (UroToday.com) - Presented by Anthony M. Joshua,1 Neal Shore,2 Fred Saad,3 Kim N. Chi,4 Carl A. Olsson,5 Urban Emmenegger,6 Mark Scholz,7 William Berry,8 Som D. Mukherjee,9 Eric Winquist,10 Naomi B. Haas,11 Nahla Hasabou,12 Carl Dmuchowski,12 Frank Perabo,12 Mohammad Hirmand,13 Margaret A. Foley,12 and Dana Rathkopf,14 for The Enzalutamide Expanded Access Study Investigators at the American Society of Clinical Oncology (ASCO) 50th Annual Meeting - May 30 - June 3, 2014 - Chicago, Illinois USA

    Published June 3, 2014
  • A comprehensive review of genomic landscape, biomarkers and treatment sequencing in castration-resistant prostate cancer.

    Hormone-naïve prostate cancer and its castration-resistant state (CRPC) are clinically and genetically heterogeneous diseases. From initiation of prostate carcinogenesis to its evolution towards therapeutic resistance, various combinations of genetic and epigenetic events occur.

    Published June 22, 2016
  • A randomized Phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN).

    Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second line. Vinflunine is the only treatment approved in this setting by the European Medicines Agency (EMA) and taxanes are also widely used in second line.

    Published April 28, 2017
  • Activity of cabazitaxel in patients with metastatic castration-resistant prostate cancer after treatment with single or dual regimens of novel androgen receptor-targeting agents.

    The purpose of this study was to evaluate the efficacy of cabazitaxel for patients with metastatic castration-resistant prostate cancer (mCRPC) after sequential therapy with docetaxel (DTX) and single or dual regimens of novel androgen receptor-axis-targeted (ARAT) agents.

    Published August 24, 2017
  • An overview of current and emerging therapeutic management strategies for patients with metastatic castration-resistant prostate cancer, "Beyond the Abstract," by Joelle El-Amm, MD and Jeanny Aragon-Ching, MD

    BERKELEY, CA (UroToday.com) - The treatment of metastatic castrate resistant prostate cancer (mCRPC) has changed drastically over the past few years with the emergence of several new therapies.

    Published July 12, 2013
  • ASCO 2013 - Podcast: CRPC: The place of novel agents focused on the androgen axis

    CHICAGO, IL USA (UroToday.com) - Presented by William K. Oh, MD at the American Society of Clinical Oncology (ASCO) Annual Meeting - May 31 - June 4, 2013 - McCormick Place - Chicago, IL USA

    Published June 10, 2013
  • ASCO 2013 - Slide Presentation: CRPC: The place of novel agents focused on the androgen axis

    CHICAGO, IL USA (UroToday.com) - Presented by William K. Oh, MD at the American Society of Clinical Oncology (ASCO) Annual Meeting - May 31 - June 4, 2013 - McCormick Place - Chicago, IL USA

    Published June 10, 2013
  • AUA 2013 - Session Highlights: AUA Guidelines: Castration Resistant Prostate Cancer

    SAN DIEGO, CA USA (UroToday.com) - Michael Cookson, MD, Vice Chair and Professor of Urologic Surgery at Vanderbilt, presented the first AUA guideline for the management of castration-resistant prostate cancer, a lethal form of the disease.

    Published May 8, 2013
  • Cabazitaxel and silibinin co-encapsulated cationic liposomes for CD44 targeted delivery: A new insight into nanomedicine based combinational chemotherapy for prostate cancer.

    Cancer stem cells (CSCs) are the promising targets for cancer chemotherapy that cannot be eliminated by conventional chemotherapy. In this study cationic liposomes of cabazitaxel (CBX) and silibinin (SIL) were prepared with an aim to kill cancer cells and CSCs for prostate cancer.

    Published December 19, 2018
  • Cabazitaxel regimens inhibit the growth of prostate cancer cells and enhances the anti-tumor properties of PEDF with various efficacy and toxicity.

    Taxanes chemotherapies represent the major therapeutic alternative for symptomatic mCRPC. While docetaxel is the most commonly prescribed Taxane for mCRPC; cabazitaxel has been approved for patients unresponsive to docetaxel.

    Published May 16, 2018
  • Clinical concepts for cabazitaxel in the management of metastatic castration-resistant prostate cancer.

    Prostate cancer is the most common malignancy in male patients. The second-generation taxanes, cabazitaxel, is a therapeutic option with an overall survival advantage for patients with metastatic castration-resistant prostate cancer.

    Published August 5, 2019
  • Clusterin knockdown sensitizes prostate cancer cells to taxane by modulating mitosis.

    Clusterin (CLU) is a stress-activated molecular chaperone that confers treatment resistance to taxanes when highly expressed. While CLU inhibition potentiates activity of taxanes and other anti-cancer therapies in preclinical models, progression to treatment-resistant disease still occurs implicating additional compensatory survival mechanisms.

    Published May 26, 2016
  • Complete response with early introduction of cabazitaxel in a patient with multiple lung metastases of castration-resistant prostate cancer following the early detection of metastases using liquid biopsy: a case report.

    Cabazitaxel (CBZ) chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) is believed to be palliative because the radiological response rate is low and a durable response is rare. Here, we describe a rare case of a patient with mCRPC who was treated with CBZ chemotherapy and showed a durable radiological response and a complete biochemical response.

    Published June 20, 2019
  • Correlation between Automated Bone Scan Index Change after Cabazitaxel and Survival among Men with Castration-Resistant Prostate Cancer.

    Automated bone scan index (aBSI) change (ΔBSI) after treatment and survival in men with prostate cancer remains unclear. We evaluated the correlation between ΔBSI after cabazitaxel and overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (CRPC).

    Published August 29, 2019
  • Current therapeutic options in metastatic castration-resistant prostate cancer.

    The tumors of many patients with prostate cancer eventually become refractory to androgen deprivation therapy with progression to metastatic castration-resistant disease. Significant advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have been made in recent years, and new treatment strategies have recently been made available.

    Published November 21, 2018
  • Effects of Cabazitaxel in Renal Cell Carcinoma Cell Lines.

    Advanced renal cell carcinoma is treated with mammalian target of rapamycin (mTOR) inhibitors or tyrosine kinase inhibitors (TKIs). The effects of these drugs are, however, limited and novel treatment strategies are required.

    Published December 9, 2015
  • Efficacy and safety of 4-weekly cabazitaxel for castration-resistant prostate cancer: a multi-institutional study.

    This study aimed to reveal the efficacy and safety profiles of 4-weekly cabazitaxel in patients with castration-resistant prostate cancer (CRPC).

    The study included 62 Japanese patients who were treated for CRPC with ≥ 2 courses of cabazitaxel between 2014 and 2017.

    Published May 31, 2019
  • Efficacy and safety of abiraterone acetate plus prednisone vs. cabazitaxel as a subsequent treatment after first-line docetaxel in metastatic castration-resistant prostate cancer: results from a prospective observational study (CAPRO).

    To describe the patterns of second-line treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) after docetaxel treatment in a Spanish population, to identify the factors associated with those patterns, and to compare the efficacy and safety of the treatments most frequently administered.

    Published August 12, 2019
  • Efficacy of Cabazitaxel in Castration-resistant Prostate Cancer Is Independent of the Presence of AR-V7 in Circulating Tumor Cells.

    Androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) was recently demonstrated to be associated with resistance to abiraterone and enzalutamide.

    Published September 4, 2015
  • Interim analysis of the REASSURE (Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation) study: patient characteristics and safety according to prior use of chemotherapy in routine clinical practice.

    REASSURE is a global, prospective, non-interventional study to assess long-term safety of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Here we report an interim analysis of patients according to previous use of chemotherapy.

    Published April 10, 2019
  • Mechanism of paclitaxel resistance in a human prostate cancer cell line, PC3-PR, and its sensitization by cabazitaxel.

    Paclitaxel (PTX) is a microtubule-targeting drug widely used for the treatment of a variety of cancers. However, drug resistance can emerge after a series of treatments, and this can seriously affect the patient's prognosis.

    Published October 4, 2016
  • No significant impact of prior treatment profile with docetaxel on the efficacy of cabazitaxel in Japanese patients with metastatic castration-resistant prostate cancer.

    The objective of this study was to retrospectively analyze the oncological outcomes of Japanese patients with metastatic castration-resistant prostate cancer (mCRPC) who received cabazitaxel. This study included a total of 63 consecutive Japanese mCRPC patients treated with cabazitaxel following the failure of docetaxel, and assessed the prognostic significance of cabazitaxel therapy in these patients focusing on the association of efficacies between two taxane agents.

    Published July 28, 2017
  • Oncologic Response and Hospitalization Rate of Patients Receiving Cabazitaxel in the Fourth-Line and Beyond in Castration-Resistant Prostate Cancer: Analysis of a Retrospective Cohort and a Structured Literature Review.

    Limited data are available for the use of agents in metastatic castration-resistant prostate cancer (mCRPC) beyond the third-line. We provide data during treatment with cabazitaxel (CAB), helping to improve the informed-consent process.

    Published July 20, 2017
  • Patient characteristics and overall survival in patients with post-docetaxel metastatic castration-resistant prostate cancer in the community setting.

    It is unclear how treatment sequencing for metastatic castration-resistant prostate cancer (mCRPC) affects real-world patient outcomes. We assessed treatment sequences, patient characteristics and overall survival (OS) in post-docetaxel mCRPC patients.

    Published August 16, 2017
  • Phase 2 Study of Cyclophosphamide, Etoposide, and Estramustine in Patients With Castration-Resistant Prostate Cancer.

    There are no effective chemotherapies for patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease has failed to respond to taxanes or patients who do not wish to receive intravenous drugs.

    Published August 6, 2018
  • Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone.

    Background: Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label Phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (Phase I), and after docetaxel and abiraterone (Phase II) (NCT01511536).
    Published November 1, 2016
  • Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA).

    Noninvasive biomarkers are needed to guide metastatic castration-resistant prostate cancer (mCRPC) treatment.

    To clinically qualify baseline and on-treatment cell-free DNA (cfDNA) concentrations as biomarkers of patient outcome following taxane chemotherapy.

    Published March 5, 2018
  • 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
  • Prostate-specific antigen doubling time and response to cabazitaxel in a hormone-resistant metastatic prostate cancer patient.

    We report a case of metastatic castration-resistant prostate cancer, who received prior treatment with docetaxel and was then given cabazitaxel as salvage therapy. The patient was monitored by prostate-specific antigen doubling time and prostate-specific antigen absolute value.

    Published October 19, 2015
  • Quality of Life in Second-Line Treatment of Metastatic Castration-Resistant Prostate Cancer Using Cabazitaxel or Other Therapies After Previous Docetaxel Chemotherapy: Swiss Observational Treatment Registry.

    The aim was to evaluate quality of life (QoL), pain, and fatigue in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with different regimens after first-line docetaxel, as well as disease progression.

    Published October 4, 2017
  • Researchers reveal underlying mechanism of powerful chemotherapy for prostate cancer treatment

    NEW YORK, NY USA (Press Release) - September 17, 2012 -

    Study Suggests Role of Taxane-Based Chemotherapy Drugs May Be Underestimated and Should Be Re-examined to Improve the Drug's Effectiveness

    The power of taxane-based chemotherapy drugs are misunderstood and potentially underestimated, according to researchers at Weill Cornell Medical College in the September 15 issue of the journal Cancer Research.

    Most physicians and investigators believe that taxane chemotherapy (paclitaxel, docetaxel and cabazitaxel) just does one thing — stop a cancer cell from dividing — but the team of Weill Cornell scientists have revealed it acts much more powerfully and broadly, especially against prostate cancer.

    "Taxanes are one of the best class of chemotherapy drugs that we can use to treat our cancer patients, but while they are effective against a wide range of tumors, they don't work in all of them, and often patients become resistant," says the study's senior investigator, Dr. Paraskevi Giannakakou, an associate professor of pharmacology in medicine and pharmacology and director of laboratory research for the Division of Hematology and Medical Oncology at Weill Cornell. "However, our new understanding of the precise action of taxanes in a cancer cell may help us overcome drug insensitivity or acquired resistance to the drugs and design therapies that can be used in combination with them to improve cancer control."

    In their study, the researchers stress that investigators must shift their attention away from taxane's function during cell division to the drugs' effects on halting the everyday movement of proteins and protein-to-protein communication within cancer cells — and to understanding how and why a cancer cell can still survive. Researchers suggest that cancers that are insensitive to taxanes — or those that have become resistant to them — may, for example, switch to alternate forms of "transportation" to shuttle proteins within cells in a way that does not depend on the cell's skeletal structure which is the target of taxane therapy.

    Researchers showed in the study that the androgen receptor (AR), which is a driving force in prostate cancer growth and metastasis, "moves" along microtubules to be transported to the nucleus. When a taxane binds microtubules, it stops AR from traveling, thus inhibiting its activity. Taxane chemotherapy drugs such as paclitaxel, docetaxel and cabazitaxel work by binding tubulin, a protein that makes up microtubules. Microtubules are the rope-like channels that provide both a skeletal structure to cells as well as provide "highways" along which molecules, such as proteins, RNA complexes and vesicles, can travel from one part of the cell to another and interact with each other.

    "Microtubules are the highly dynamic network of wires within cells, and when taxanes are used, the network stops moving," says Dr. Giannakakou. This is best observed when cancer cells attempt to divide, she says. "It is easy to see in the laboratory, that prostate cancer cells double every 30-48 hours, and taxane stops them from doing that, which pushes these cells to die. This leads everyone to think that this is exclusively how taxanes work – they stop cells from dividing."

    But Dr. Giannakakou and her research team point out in their new study that patients have significantly lower rates of cell division in their tumors than do cancer cells growing in the lab. In fact, cancer cells in prostate cancer patients only divide every 33-577 days, she says. "Thus, the therapeutic benefit of taxanes on microtubules depends on more than just stopping cell division."

    The new insights provided by this study about the action of taxanes on AR trafficking helps explain the clinical activity of these drugs in the treatment of prostate cancer while at the same time can help researchers better understand why an individual patient might respond or not to taxane therapy. Such insights are critical for future chemotherapy customization, according to researchers.

    The drug that was later named Taxol (pacilitaxel) was isolated from the bark of a Pacific yew tree by federal researchers in 1967 and was later synthesized. It 1993 it was approved for use in ovarian cancer, and has since been used for lung, breast, head and neck and other cancers. Taxotere (docetaxel), synthesized from chemicals extracted from the European yew tree, was developed as an alternative to Taxol, and is used for the treatment of many of the same cancer types. Cabazitaxel, the newest taxane, is a semi-synthetic paclitaxel analog and is used to treat patients with prostate cancer who have failed prior docetaxel chemotherapy.

    "In the 20 years since Taxol was approved, hundreds of labs worldwide are trying to understand how taxanes work to stop cell division in cancer," Dr. Giannakakou says. "However, we think they need to now take a fresh approach and look at what these drugs do during the normal life cycle of a cancer cell and target the newly revealed underlying mechanisms and modes of movement with novel therapies, in combination with taxane therapy, to provide life-saving therapy for patients who don't benefit from taxanes."

    Investigators working with Dr. Giannakakou on the study are the first author Maria Thadani-Mulero, who is a graduate student enrolled at Surrey University, UK performing her thesis work in Dr. Giannakakou's laboratory, and Dr. David M. Nanus, the Mark W. Pasmantier Professor of Hematology and Oncology in Medicine and chief of the Division of Hematology and Medical Oncology at Weill Cornell.

    This study was funded by grants from the National Institutes of Health, the National Cancer Institute's Physical Sciences-Oncology Center at Cornell University, the Weill Cornell Clinical and Translational Science Center, a Creativity Award from the Prostate Cancer Foundation, and support from the Genitourinary Oncology Research Fund.

    Weill Cornell Medical College

    Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.

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    Published September 18, 2012
  • Risk stratification of castration-resistant prostate cancer patients treated with cabazitaxel.

    Patient characteristics before administering the first cycle of cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC) were collected to assess prognostic factors for overall survival (OS).

    Published December 21, 2018
  • Role of taxanes in advanced prostate cancer.

    Advanced prostate cancer is an androgen-dependent disease for which the initial treatment is an androgen deprivation maneuver. However, some primary resistances to hormonal treatment occur with increasing incidence throughout the evolution of the disease.

    Published February 24, 2016
  • Safety and efficacy of cabazitaxel in 660 patients with metastatic castration-resistant prostate cancer in real-world settings: results of a Japanese post-marketing surveillance study.

    To evaluate the real-world safety and efficacy of cabazitaxel in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen.

    Published August 2, 2019
  • Sequencing new agents after docetaxel in patients with metastatic castration-resistant prostate cancer.

    Two new hormonal agents (NHAs), abiraterone and enzalutamide, and one chemotherapeutic agent, cabazitaxel (CABA) improved overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress after docetaxel.

    Published September 17, 2015
  • Slide Lecture: Immunotherapy and vaccines in castration resistant prostate cancer: What do we know so far and clinical applications

    BERKELEY, CA (UroToday.com) - Presented by James L. Gulley, MD, PhD, FACP

    Published June 14, 2013
  • Splice Variants of Androgen Receptor and Prostate Cancer.

    Over the last ten years, two new-generation hormonal drugs and two chemotherapeutic agents have been approved for the treatment of metastatic castration-resistant prostate cancer. Unfortunately, some patients have primary resistance to them and the others eventually develop secondary resistance.

    Published August 3, 2016
  • The efficacy and safety comparison of docetaxel, cabazitaxel, estramustine, and mitoxantrone for castration-resistant prostate cancer: A network meta-analysis.

    The aim of this study was to compare the efficacy and safety of docetaxel, cabazitaxel, docetaxel + estramustine, mitoxantrone in the management of castration-resistant prostate cancer (CRPC).

    Published June 19, 2018
  • The evolving role of chemotherapy in prostate cancer.

    Despite extensive clinical research of different chemotherapy agents for more than three decades, the role of chemotherapy in prostate cancer was only established in 2004, after demonstrating a survival benefit with docetaxel in metastatic castration-resistant prostate cancer.

    Published January 27, 2017
  • The Influence of Prednisone on the Efficacy of Cabazitaxel in Men with Metastatic Castration-Resistant Prostate Cancer.

    Background: Cabazitaxel is a second-generation taxane that is approved for use with concomitant low dose daily prednisone in metastatic castration resistant prostate cancer (mCRPC) after docetaxel failure.

    Published September 29, 2017
  • The prognostic significance of grade 3/4 neutropenia in Japanese prostate cancer patients treated with cabazitaxel.

    The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen.

    Published March 9, 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).

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    Published June 23, 2014
  • 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
  • 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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