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mCRPC Treatment COE

  • A prospective study examining elder-relevant outcomes in older adults with prostate cancer undergoing treatment with chemotherapy or abiraterone.

    BACKGROUND - Treatment of metastatic castration-resistant prostate cancer (mCRPC) with chemotherapy improves disease control and survival in fit older men (age 65+) but its impact on function is not clear. We hypothesized that chemotherapy would impair daily function in older men with mCRPC.

    Published February 24, 2016
  • Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer

    BACKGROUND: Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer.
    Published June 5, 2017
  • ASCO 2017: A phase II trial of abiraterone acetate (AA) without prednisone in castration resistant prostate cancer (CRPC)

    Chicago, IL (UroToday.com) Abiraterone acetate, a CYP17A inhibitor, is now a well-established treatment option for metastatic castration-resistant prostate cancer (mCRPC), regardless of prior docetaxel chemotherapy treatment, based on the results of the COU-AA-301 and COU-AA-302 studies.1,2 Enzalutamide, a novel androgen axis inhibitor, was introduced as a treatment for mCRPC around the same time, and has been a competitor in the same disease space.
    Published June 6, 2017
  • ASCO 2017: A phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer

    Chicago, IL (UroToday.com) Selecting the appropriate sequence and combination of therapy for metastatic castration-resistant prostate cancer (mCRPC) is challenging. At the ASCO 2017 prostate cancer poster session, Dr. Thomas Powles and colleagues presented their study design for a phase III trial comparing atezolizumab with enzalutamide versus enzalutamide alone in patients with mCRPC (IMbassador250 Trial).
    Published June 6, 2017
  • ASCO 2017: A randomized phase II cross-over study of abiraterone + prednisone vs enzalutamide for patients with metastatic, castration-resistant prostate cancer

    Chicago, IL (UroToday.com) Dr. Chi and colleagues presented results of their randomized phase II trial of abiraterone + prednisone vs enzalutamide among patients with metastatic castration-resistant prostate cancer (mCRPC) at today’s prostate cancer oral abstract session at the 2017 ASCO annual meeting in Chicago. This is a crucial study, considering that both medications are indicated as first line therapy for men with mCRPC, however they have not been directly compared and the optimal treatment sequencing has not yet been elucidated.
    Published June 3, 2017
  • ASCO 2017: Adding abiraterone for men with high-risk prostate cancer starting long-term androgen deprivation therapy: Survival results from STAMPEDE

    Chicago, IL (UroToday.com) The management of newly metastatic prostate cancer has traditional been androgen-deprivation therapy (ADT), and until this decade, patients who failed ADT went on to receive chemotherapy. With the influx of new treatment options for castration-resistant prostate cancer (CRPC), there has been growing interest in assessing whether these novel therapies may be beneficial up front. The CHAARTED study demonstrated the benefit of ADT and docetaxol chemotherapy for newly metastatic prostate cancer, particularly in patients with high volume disease.
    Published June 3, 2017
  • ASCO 2017: Androgen deprivation therapy in the treatment of prostate cancer and dementia risk: A systematic review and meta-analysis

    Chicago, IL (UroToday.com) Since the introduction of the concept of castration as a treatment for advanced or metastatic prostate cancer (PCa) by Huggins & Hodges in 1941, castration and subsequently androgen deprivation therapy (ADT) have remained the standard first-line therapy for metastatic PCa.
    Published June 6, 2017
  • ASCO 2017: ARASENS phase 3 trial of ODM-201 in men with metastatic hormone-sensitive prostate cancer

    Chicago, IL (UroToday.com) Dr. Matthew Smith and colleagues presented the design for their trial, the ARASENS phase III trial assessing ODM-201 (darolutamide) in men with metastatic hormone-sensitive prostate cancer at the prostate cancer poster session at ASCO 2017. Even with first line therapy (ADT +/- docetaxel or abiraterone, based on the LATITUDE and STAMPEDE studies presented this week), most patients with metastatic hormone-sensitive prostate cancer (mHSPC) progress to castration-resistant prostate cancer (CRPC).
    Published June 6, 2017
  • ASCO 2017: Assessment of quality of life, cognitive function and depression in a randomized phase II study of abiraterone acetate (ABI) plus prednisone (P) vs enzalutamide (ENZA) for metastatic castrate-resistant prostate cancer (mCRPC)

    Chicago, IL (UroToday.com) As enzalutamide (Enza) and abiraterone (Abi) have become mainstays of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC), a difficult clinical question has always been how to sequence these medications. In this randomized phase II clinical study, the goal is to evaluate the clinical efficacy and side effects of sequencing these two medications.
    Published June 6, 2017
  • ASCO 2017: Association of loss of tumor suppressor ZFP36 with lethal prostate cancer

    Chicago, IL (UroToday.com) Inflammation has been linked to prostate cancer (PCa) progression which may be mediated by the transcription factor nuclear factor kappa B (NFκB). Using a bioinformatic screen focused on NFκB pathway activation in lethal PCa, the authors identified the tumor suppressor ZFP36 as a key node of the NFκB network. Furthermore, the authors had shown in vitro that ZFP36 expression was inversely associated with both NFκB-controlled gene levels, and proliferation and sensitivity to enzalutamide.
    Published June 6, 2017
  • ASCO 2017: Avelumab in metastatic castration-resistant prostate cancer (mCRPC)

    Chicago, IL (UroToday.com) Avelumab, an anti-PD-L1 antibody, is one of the novel immune checkpoint inhibitors generating so much interest in the field of cancer therapy. With growing evidence for its efficacy in multiple solid malignancies, including its recent approval for the treatment of metastatic bladder cancer, there is an effort to assess these agents in the setting of castration-resistant prostate cancer.
    Published June 6, 2017
  • ASCO 2017: Baseline CTC subtype to predict outcomes on mCRPC patients receiving enzalutamide compared to abiraterone

    Chicago, IL (UroToday.com) At the prostate cancer poster session at the 2017 ASCO annual meeting, Dr. Howard Scher and colleagues presented their data regarding baseline circulating tumor cell (CTC) subtypes as a way to predict outcomes of mCRPC patients receiving enzalutamide or abiraterone.
    Published June 6, 2017
  • ASCO 2017: Challenges in Translating Molecular Results Into Meaningful Clinical Use

    Chicago, IL (UroToday.com) Dr. Pritchard of the University of Washington concluded the session “Liquid and Solid Biopsies of Metastatic Lesions: How, When, and What to do with the Results” at the 2017 ASCO annual meeting with a high-level talk discussing the challenges of translating molecular results into meaningful clinical use.
    Published June 5, 2017
  • ASCO 2017: Chemotherapy for Metastatic Castration-Resistant Prostate Cancer: Which Patient? Which Time?

    Chicago, IL (UroToday.com) At 2017 ASCO annual meeting session on “How to Integrate Multimodal Therapy Into the Management of Castration-Resistant Prostate Cancer CRPC”, Dr. Aparicio discussed the role of chemotherapy, specifically aspects regarding which patient to treat and when to treat. 
    Published June 3, 2017
  • ASCO 2017: Circulating tumour cells and survival in abiraterone and enzalutamide treated patients with castration-resistant prostate cancer

    Chicago, IL (UroToday.com) Dr. De Laere presented a study investigating the prognostic value of circulating tumor cells (CTC) enumeration and dynamics in the context of second-line endocrine therapies (i.e. abiraterone or enzalutamide) in patients with metastatic castrate-resistant prostate cancer (mCRPC). 
    Published June 6, 2017
  • ASCO 2017: Clinical activity and safety of ASN001, a selective CYP17 lyase inhibitor, administered without prednisone in men with metastatic castration-resistant prostate cancer (mCRPC): A phase 1/2 clinical trial.

    Chicago, IL (UroToday.com) Abiraterone acetate, a CYP17A inhibitor, is now a well-established treatment option for metastatic castration-resistant prostate cancer (mCRPC), regardless of prior docetaxel chemotherapy treatment, based on the results of the COU-AA-301 and COU-AA-302. studies.1,2 However, abiraterone administration was approved along with the administration of prednisone 5 mg twice daily, due to the risk of mineralocorticoid excess from suppression of the glucocorticoid synthesis.
    Published June 6, 2017
  • ASCO 2017: Clinical Implications of Genomic Sequencing in Prostate Cancer

    Chicago, IL (UroToday.com) Dr. Heather Cheng gave a short introduction before giving an excellent summary of abstracts 5009, 5010 and 5011. Nowadays there are many life prolonging treatments for metastatic castrate resistant prostate cancer (mCRPC), and more in development. Genomic sequencing is advancing in tremendous steps but is still not a standard in prostate cancer. It is however known, that mCRPC has >20% defects in DNA repair genes (BRCA1-2, ATM and more) and >10% of DNA repair defects are germline (heritable). Lastly, treatment with androgen receptor (AR) targeted agents can select for more aggressive variants. 
    Published June 6, 2017
  • ASCO 2017: Clinical outcome of metastatic castration-resistant prostate cancer patients with a post-treatment circulating tumor cell of 0 vs CTC > 0: Post hoc analysis of COU-AA-301.

    Chicago, IL (UroToday.com) Assessment of radiographic response by RECIST in the majority of metastatic castration-resistant prostate cancer (mCRPC) patients is limited by the lack of measurable disease. It is known that changes in circulating tumor cell (CTC) counts enumerated using Cellsearch from patients with unfavorable counts at baseline ( [≥ 5 cells/7.5 mL]) to favorable counts (≤ 4) are prognostic for survival.
    Published June 6, 2017
  • ASCO 2017: Emerging Biomarkers of Chemotherapy Resistance

    Chicago, IL (UroToday.com) Dr. Karen Knudsen gave a summary of abstracts 5012, 5013, and 5014. She began with a short introduction on metastatic castrate resistant prostate cancer (mCRPC), emphasizing that strategies are needed to personalize medicine in this entity. At this point in time all mCRPC patients are treated similarly. Importantly, one should know that mCRPC is incurable and that resistance to first line hormonal therapy ultimately develops. The key questions are: Who is the right patients to receive novel therapy? What is the optimal sequencing of these agents and does it matter? For how long are these agents to be given and if they are beneficial? Why is there still relapse?
    Published June 6, 2017
  • ASCO 2017: Have Decisions by the National Institute for Health and Care Excellence Affected Outcomes of British Patients With Metastatic Castration-Resistant Prostate Cancer?

    Chicago, IL (UroToday.com) John Graham gave an excellent talk regarding the role of NICE (National Institute for Health and Care Excellence) in the drug therapeutic approval process in the setting of metastatic castration-resistant prostate cancer (mCRPC). His summary of the role of NICE as it relates to the National Health Service (NHS) in England and the UK provides a nice contrast to the drug approval process here in the United States.
    Published June 6, 2017
  • ASCO 2017: Identification of a CTC-based gene expression signature predicting resistance to abiraterone and enzalutamide in mCRPC

    Chicago, IL (UroToday.com) Dr. Todd Morgan and collaborators presented their work at the ASCO 2017 prostate cancer poster session assessing a circulating tumor cell (CTC)-based gene expression signature predicting resistance to abiraterone and enzalutamide in mCRPC patients.
    Published June 6, 2017
  • ASCO 2017: LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer

    Chicago, IL (UroToday.com) Dr. Fizazi and colleagues presented their much anticipated results from the LATITUDE trial at the 2017 ASCO annual meeting’s plenary session. In a phase III, double-blind, randomized setting, LATITUDE tested androgen deprivation therapy (ADT) with abiraterone acetate (AA) plus prednisone vs ADT + placebo in newly diagnosed high-risk metastatic hormone-naïve prostate cancer patients.
    Published June 5, 2017
  • ASCO 2017: Phase 1b/2 keynote-365 trial: Pembrolizumab (pembro) combination therapy in metastatic castration-resistant prostate cancer

    Chicaco, IL (UroToday.com) Dr. Evan Yu and colleagues presented their trial design for KEYNOTE-365, a phase Ib/II trial assessing pembrolizumab combination therapy for metastatic castration-resistant prostate cancer (mCRPC) at the prostate cancer sessions at the 2017 ASCO annual meeting. We know that approved treatments for mCRPC (eg, enzalutamide and docetaxel) may increase programmed death ligand 1 (PD-L1) expression and facilitate neoantigen release. Furthermore, olaparib, a PARP inhibitor, has shown activity in mCRPC with DNA-repair defects. The objective of this study is to evaluate the safety and efficacy of pembrolizumab with olaparib (cohort A), docetaxel + prednisone (cohort B), or enzalutamide (cohort C) in mCRPC patients.
    Published June 6, 2017
  • ASCO 2017: Phase 2 biomarker-driven study of ipilimumab plus nivolumab (Ipi/Nivo) for ARV7-positive metastatic castrate-resistant prostate cancer (mCRPC)

    Chicago, IL (UroToday.com) Novel therapies in prostate cancer are rapidly developing. Immune checkpoint inhibitors (ICI’s) are a novel class of medications that have gained a lot of interest. With efficacy established in multiple other malignancies, its role in prostate cancer is still being determined. By blocking the immune checkpoint cascade, these agents enable a patient’s own immune system to overcome cancer’s immune evasion mechanism.
    Published June 6, 2017
  • ASCO 2017: Post hoc analysis of a phase III study to test the association between circulating methylated glutathione s transferase (mGSTP1) DNA levels and response to docetaxel in metastatic castration resistant prostate cancer

    Chicago, IL (UroToday.com) Glutathione S-transferase (GSTP1) inactivation is associated with CpG island hypermethylation in > 90% prostate cancers. Detection of circulating mGSTP1 DNA predicts response to Docetaxel (DTX) and overall survival (OS) in phase I/II mCRPC cohorts. Dr. Mahon presented data from a post hoc analysis of a phase III study aiming to test the association between circulating mGSTP1 DNA levels and outcomes after 2 cycles of docetaxel (PRECYC3). The secondary objective was to see if baseline mGSTP1 predicts overall survival. 
    Published June 6, 2017
  • ASCO 2017: PROfound: A randomized Phase III trial evaluating olaparib in patients with metastatic castration-resistant prostate cancer and a deleterious homologous recombination DNA repair aberration

    Chicago, IL (UroToday.com) The genetic landscape for men with metastatic castration resistant prostate cancer (mCRPC) is rapidly evolving. At the 2017 ASCO prostate cancer poster session, Dr. Johann De Bono and colleagues presented their phase III trial design for PROfound, an evaluation of olaparib in patients with mCRPC and a deleterious homologous recombination DNA repair aberration. There are available agents that may be offered with limited therapeutic benefit for these patients, however no molecularly stratified treatment has been approved for this heterogeneous disease.
    Published June 6, 2017
  • ASCO 2017: Serum androgens and survival in metastatic castration resistant prostate cancer patients treated with docetaxel and prednisone: Results from CALGB 90401 (Alliance)

    Chicago, IL (UroToday.com) Higher baseline androgens have been previously shown to be associated with an improved overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with the androgen synthesis inhibitors, ketoconazole or abiraterone. This analysis was performed to determine whether baseline serum androgen levels Testosterone (Testo), Androstenedione (Andro) and DHEA are associated with OS in mCRPC patients treated with docetaxel-based chemotherapy. 
    Published June 6, 2017
  • ASCO 2017: Stereotactic Body Radiation: What Is Its Role in Advanced Disease?

    Chicago, IL (UroToday.com) Dr. Tran started off the “How to Integrate Multimodal Therapy Into the Management of Castration-Resistant Prostate Cancer” session at the ASCO 2017 annual meeting with his talk on the role of stereotactic body radiation in advanced disease. 
    Published June 3, 2017
  • ASCO 2017: Targeting DNA Repair Mutations in Metastatic Castration-Resistant Prostate Cancer

    Chicago, IL (UroToday.com) Dr. Johann De Bono from London, UK presented the final talk of the “How to Integrate Multimodal Therapy Into the Management of Castration-Resistant Prostate Cancer (CRPC)” at the 2017 ASCO annual meeting session. His presentation was assessing DNA repair mutations among men with CRPC.
    Published June 3, 2017
  • ASCO 2017: Targeting the AR: Biomarkers and Novel Therapeutic Approaches

    Chicago, IL (UroToday.com) Dr. Terence Friedlander focused on targeting the androgen receptor (AR), with an emphasis on biomarkers and novel therapeutic approaches. In the setting of metastatic prostate cancer (PCa), androgen deprivation therapy (ADT) remains the standard of care.
    Published June 6, 2017
  • ASCO 2017: The aggressive variant prostate carcinoma molecular signature (-MS) and platinum-sensitivity in castration resistant prostate cancer

    Chicago, IL (UroToday.com) The aggressive variant prostate cancer (AVPC) are a subset of prostate cancers that share the clinical, therapy response, and molecular profiles of the small cell prostate carcinomas, a histological variant of the disease that responds poorly to androgen receptor directed therapies.
    Published June 6, 2017
  • ASCO 2017: The plasma lipidome in castration-resistant prostate cancer

    Chicago, IL (UroToday.com) Biomarker studies of metastatic castration-resistant prostate cancer (mCRPC) have mainly focused on changes in the cancer, however, the host environment and its interactions with cancer is increasingly important, especially given the increasing association of prostate cancer (PC) outcomes and obesity. However, the association of circulating lipids with the clinical outcome of CRPC is unknown and has not been studied. Dr. Lisa Horvath presented an interesting study attempting to find associations between the plasma lipidome and clinical outcome in CRPC. 
    Published June 6, 2017
  • ASCO 2017: Whole blood androgen receptor variant expression and overall survival in metastatic castrate resistant prostate cancer

    Chicago, IL (UroToday.com) The detection of full length androgen receptor (AR-FL) or AR variants (AR-Vs) in blood and association with outcomes in metastatic castrate-resistant prostate cancer (mCRPC) is unknown. Dr. Karthik Giridhar presented a study comparing whole blood mRNA expression of AR-FL and AR-Vs to circulating tumor cells (CTCs) for predicting overall survival (OS) and time to treatment failure (TTF). 
    Published June 6, 2017
  • ASCO 2018: Sipuleucel-T OS and Clinical Outcomes by Baseline PSA Quartiles in Patients with mCRPC: PROCEED Registry

    Chicago, IL (UroToday.com) Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic/minimally symptomatic men with metastatic castration-resistant prostate cancer (mCRPC). The seminal phase III clinical trial leading to FDA approval of Sipuleucel-T was the IMPACT trial, randomizing 512 men with mCRPC in a 2:1 ratio to receive Sipuleucel-T (n=341) or placebo (n=171)1. The primary endpoint was overall survival (OS), analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum PSA and lactate dehydrogenase.
    Published June 4, 2018
  • ASCO GU 2016 Among Treated Men with mCRPC, Researchers Find More Gaps in Refills with Enzalutamide Than Abiraterone - Session Highlights (Updated)

    San Francisco, CA USA (UroToday.com) Researchers who examined treatment adherence among men with metastatic castration-resistant prostate cancer (mCRPC) who were treated with enzalutamide or abiraterone acetate, found significantly higher rates of refill gaps of 30- or 60- days or longer among enzalutamide-treated patients. This finding, from a retrospective analysis reported at the 2016 ASCO Genitourinary

    Published January 18, 2016
  • ASCO GU 2016 Clinicians’ attitudes and preferences in choosing the first line drug for mCRPC: Preliminary results from a multicenter Italian study after the introduction of abiraterone acetate (AA)

    San Francisco, CA USA (UroToday.com) Caffo and colleagues presented abstract 332 describing the way physicians in Italy choose between abiraterone acetate and docetaxel for first line treatment of metastatic castration-resistant prostate cancer (mCRPC). The study did not include enzalutamide as this was not available in Italy at the time of the study.   

    Published January 18, 2016
  • ASCO GU 2016 Large Study Reveals Significant Glucocorticoid Use in Both Treated and Untreated Prostate Cancer Patients - Session Highlights (Updated)

    San Francisco, CA USA (UroToday.com) In an analysis of a very large database to elucidate the prevalence of glucocorticoid use among both treated and untreated prostate cancer patients, 70% of patients who received chemotherapy and 88% of patients receiving oral therapies (abiraterone and enzalutamide) for metastatic disease also received glucocorticoids (GC). Approximately 30% of untreated patients and 40% of treated patients were prescribed glucocorticoids during a period of observation, according to a large review of over 300,000 cases recently reported at the 2016 ASCO Genitourinary Cancers Symposium.1 

    Published January 18, 2016
  • ASCO GU 2016 More CNS Events With Enzalutamide Vs. Bicalutamide Treatment of mCRPC - Session Highlights

    San Francisco, CA USA (UroToday.com). Among men with metastatic castration-resistant prostate cancer (mCRPC) who were initiated on enzalutamide or bicalutamide treatment, more central nervous system (CNS) events occurred with enzalutamide, even when investigators controlled for metastatic status, in a first-time “real world” examination of this issue.1 (The phase II TERRAIN study previously demonstrated a statistically significant increase in progression-free survival with enzalutamide versus bicalutamide in men with mCRPC.)2

    Published January 18, 2016
  • ASCO GU 2018: Impact Of Statins On Outcomes In Patients With mCRPC: COU-AA-301 and COU-AA-302 Trials.

    San Francisco, CA (UroToday.com) Retrospective database studies have suggested that statins may have a chemo-preventative impact on metastatic castrate resistant prostate cancer (mCRPC) pts treated with prednisone (P)/abiraterone (AA).
    Published February 9, 2018
  • ASCO GU 2018: Lu-177-labeled PSMA-I&T Radioligand Therapy for mCRPC

    San Francisco, CA (UroToday.com) The authors of this study aimed to report their clinical experience with 177Lutetium-labeled prostate-specific membrane antigen-ligand (177Lu-PSMA-I&T) for systemic radioligand therapy in 100 consecutive patients with metastatic castration-resistant prostate cancer (mCRPC).
    Published February 9, 2018
  • ASCO GU 2018: Statin use and Outcomes of Patients with mCRPC Being Treated with Abiraterone

    San Francisco, CA (UroToday.com) Epidemiologic studies have demonstrated an association between statin use and improved prostate cancer specific mortality. Several different biologic mechanisms for such an effect have been proposed, including a potential role in reducing androgen precursor bioavailability. The authors have hypothesized that statins may therefore improve outcomes specifically in patients treated with the CYP17 inhibitor Abiraterone (ABI). Di Lorenzo (2017) recently published an analysis of 187 pts showing a relationship between ABI and improved survival (OS).
    Published February 9, 2018
  • ASCO GU 2019: TALAPRO-2: A Two-Part, Placebo-Controlled Phase III Study of Talazoparib with Enzalutamide in Metastatic Castration-Resistant Prostate Cancer

    San Francisco, CA (UroToday.com) Enzalutamide is an androgen-axis targeted therapy with established efficacy in the treatment of advanced prostate cancer (PCa), including metastatic castration-resistant PCa (mCRPC) and non-metastatic CRPC (nmCRPC).
    Published February 17, 2019
  • Astellas and Pfizer Announce Positive Top-Line Results from Phase 3 ARCHES Trial of XTANDI® (enzalutamide) in Men with Metastatic Hormone-Sensitive Prostate Cancer

    San Francisco, CA USA (UroToday.com) -- Astellas Pharma Inc. President and CEO: Kenji Yasukawa, Ph.D., and Pfizer Inc. announced that the Phase 3 ARCHES trialevaluating XTANDI® (enzalutamide) plus androgen deprivation therapy (ADT) in men with metastatic hormone-sensitive prostate cancer (mHSPC) met its primary endpoint, significantly improving radiographic progression-free survival (rPFS) versus ADT alone. The preliminary safety analysis of the ARCHES trial appears consistent with the safety profile of XTANDI in previous clinical trials in castration-resistant prostate cancer (CRPC). Detailed results will be submitted for presentation at an upcoming medical congress.
    Published December 20, 2018
  • AUA 2016: Impact of Abiraterone Acetate in Prostate Specific AntiGEN Trial Update: Effect of abiraterone acetate and low dose prednisone on prostate-specific antigen and radiographic disease progression in patients with nmCRPC

    San Diego, California (UroToday.com): Charles Ryan, MD discussed data on the effect of abiraterone acetate and low dose prednisone on prostate-specific antigen and radiographic disease progression in patients with non-metastatic castration-resistant prostate cancer. Abiraterone acetate (AA) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).
    Published May 9, 2016
  • AUA 2018: Association of Dose Reduction of Abiraterone Acetate plus Prednisone or Enzalutamide and PSA Progression in Veterans with mCRPC

    San Francisco, CA (UroToday.com) Abiraterone acetate and enzalutamide are oral agents which have both been shown to reduce PSA, delay time to PSA progression, and prolong overall survival in men with metastatic castrate-resistant prostate adenocarcinoma (mCRPC).  Stephen Freedland, MD,  from Cedars-Sinai Medical Center, presented his group’s data evaluating the association between the dose reduction of these agents, which can sometimes be necessary in order to minimize side-effects or toxicities, and PSA progression in men with mCRPC. 
    Published May 25, 2018
  • AUA 2018: Health-Related Quality of Life in Patients with mCRPC Treated with Cabazitaxel, CAPRISTANA

    San Francisco, CA (UroToday.com) Angelika Pichler, MD from Leoben, Austria presented an international, multi-centered prospective observational study, examining health-related quality of life outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel.  Cabazitaxel is approved as a 2nd line agent for patients with mCRPC who have been previously been treated with docetaxel, which was approved following a phase III trial demonstrating an improvement over mitoxantrone by 2.4 months (p<0.0001).
    Published May 19, 2018
  • AUA 2018: Interim Analysis of an Open Label Phase II Study of Enzalutamide and Radium-233 in Symptomatic, mCRPC

    San Francisco, CA (UroToday.com) Five years ago, in a landmark trial, Radium-223 (compared to placebo) demonstrated a significant improvement in overall survival (OS) (median 14.9 months vs. 11.3 months; HR 0.70, 95%CI 0.58-0.83) among men with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases [1]. Given the plethora of treatment options that have been approved for mCRPC since the 2013 publication of the ALSYMPCA trial, there is interest in combining different therapeutic modalities with Radium-223.
    Published May 23, 2018
  • AUA 2018: The Impact of Prior Local Therapy on Overall Survival in Men with Metastatic Castration-Resistant Prostate Cancer: Results from SEARCH

    San Francisco, CA (UroToday.com) Local control for patients with metastatic prostate cancer has been increasingly considered – retrospective series and large database analyses suggest there may be some benefit to primary disease control. This may take the form of either cytoreductive prostatectomy or radiotherapy. As randomized controlled trial data is still pending (Europe’s TRoMbone and the North American NCT01751438), we are left to depend on these studies to inform our decision making. While many of the prior series focused on men with metastatic disease, none specifically assessed or included men with metastatic castration-resistant prostate cancer (mCRPC), or patients who have gone on to fail androgen deprivation therapy (ADT).
    Published May 19, 2018
  • CARG tool’s ability to predict older prostate cancer patients’ risk of toxicity: Beyond the Abstract

    Prostate cancer is one of the leading causes of cancer death in American men and mostly affects men above age 65. [1]  The American Cancer Society predicts 161,360 new cases of prostate cancer and 26,730 deaths from prostate cancer in the United States in the year 2017. [1]  Although fewer than 10% of people are diagnosed with de novo metastatic disease, many men with early stage prostate cancer will eventually develop metastatic disease. The initial treatment of metastatic disease is androgen deprivation therapy, but this is only effective for a few years, after which the disease continues to progress.  At this point it is referred to as metastatic castrate resistant prostate cancer (mCRPC).  About 10-20% of people are diagnosed with mCRPC within 5 years of a diagnosis of prostate cancer, but more than 50% of patients with mCRPC die within 3 years. [2]  mCRPC is currently defined as the progression of the prostate cancer despite castrate levels of testosterone (usually defined as <1.7nmol/L). [2]  Progression to mCRPC is typically associated with worsening symptoms, declining quality of life and worsening pain.  However, mCRPC may be helped by other forms of hormone therapy such as the androgen receptor axis-targeted (ARAT) agents Abiraterone and Enzalutamide because it is not completely hormone-refractory. [3]  Patients who become resistant to ARAT therapy usually are considered for chemotherapy. [4]  In 2004, docetaxel became the standard of care for mCRPC. Later, cabazitaxel was also found to be beneficial in patients with mCRPC that progressed after receiving docetaxel therapy. [2]

    Chemotherapy

    Chemotherapy remains the treatment of choice in symptomatic mCRPC, but survival benefits after undergoing chemotherapy are modest (on the order of a few months).  In comparison to mitoxantrone (the prior standard chemotherapy agent), docetaxel was associated with better pain control, quality of life and more frequent PSA responses. [5]  However, chemotherapy can also be associated with significant toxicity, with 18-44% rates of grade 3 or higher toxicity.  National Cancer Institute Common Terminology Criteria for Adverse Events defines grade 3 as severe, grade 4 as life-threatening or disability and grade 5 as death. [6]  Common toxicities from chemotherapy include neutropenia, generalized weakness, bone pain, fatigue, peripheral edema and mucositis.  The most common grade 3 to 5 toxicities with docetaxel are: neutropenia, leucopenia, anemia, fatigue, infection and dehydration. [5]

    Currently, there is a need to find tools that can help identify men who may be more or less likely to experience serious toxicity from chemotherapy because it could help during treatment decision-making. Predicting toxicities would help doctors determine the side effects and toxicities that specific patients might develop before prescribing the treatment.  This way, it would make it easier for them to determine which treatment method would work, at which dose and method of delivery.  Making a more informed decision can be important in this setting because of the increased risk of death or functional decline.  It is especially helpful to be able to predict these toxicities in older adults because the risk of toxicity increases with age.  In practice, chemotherapy is less likely to be given to older adults due to the concerns about their ability to tolerate it. [6]  Many older adults tend to place an increasing value on avoiding treatments that adversely affect their quality of life or functional independence. [7]  Since older adults have a higher risk of toxicity and place an increasing importance on quality of life, oncologists may find it harder to suggest the best treatment option.  Hence, it would be useful to be able to predict toxicities from chemotherapy.  This advancement in toxicity prediction would also help select up-front treatment modifications such as dose reduction or the addition of colony-stimulating factors to reduce toxicity.

    Tools such as the Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 5-point scale are currently used to determine risk by assessing a patient’s level of function and capability to perform self-care.  Although this tool is a prognostic factor for survival and may help select which patients should not get chemotherapy, it is a poor predictor of toxicity risk because it is subjective, being subject to bias and high interobserver variability. [8]  Oncologist judgement in stratifying patients into those at lower or higher risk of toxicity may be better, but it has rarely been formally compared against measures such as the ECOG PS.  Finally, the agreement between currently used tools such as PS and clinical judgement by oncologists is still quite low. [9]

    Our study sought to identify tools that could help inform treatment decision-making by improving the ability to predict a patient’s risk of chemotherapy toxicity.  Distinguishing men at lower and higher risk of severe toxicity in men with mCRPC would help make better treatment decisions and allow a more informed decision about the risks and benefits of chemotherapy.  In patients with very high risks of toxicity that may counterbalance any perceived benefits, there are four main options besides conventional dose chemotherapy: (a) reduced-dose chemotherapy; (b) use of colony-stimulating factors to reduce neutropenia and related complications; (c) alternative, gentler agents or clinical trials of novel therapies; (d) best supportive care.  While our study did not focus on which treatment might be best, we sought to validate the Vulnerable Elders Survey-13 (VES-13) and Cancer and Aging Research Group (CARG) tool in mCRPC with the goal of helping a clinician’s judgment. 

    VES-13

    The VES-13 is a brief (3-4 minutes), self-report tool that measures vulnerability.  The initial purpose of developing this tool was to better screen older persons at risk of health deterioration. [10]  In the original study, vulnerable older people were defined as persons age 65 and older who were at increased risk of functional decline or death over 2 years. [10]  The instrumental activities of daily living (IADLs) and activities of daily living (ADLs) that the VES-13 focuses on include shopping, performing light housework, managing finances, preparing meals, using the telephone, bathing, dressing, transferring, toileting, walking across the room, and eating. [10]   However, its ability to predict grade 3-5 chemotherapy toxicity has yet to be studied. 

    CARG 

    The CARG tool uses a combination of 11 parameters, including age, tumor and treatment characteristics, laboratory data, and specific geriatric assessment parameters to help predict grade 3-5 chemotherapy toxicity in older patients with cancer.  It categorizes people into low, intermediate and high risk of severe chemotherapy toxicity, in our case grade 3+ chemotherapy toxicity.  It does include a geriatric assessment questionnaire with 6 domains: functional status, co-morbidity, psychological state, social activity, social support, and nutrition.  The purpose of developing the CARG tool was to identify risk factors for chemotherapy toxicity in older adults undergoing various chemotherapy regimens and create a user-friendly risk stratification schema for chemotherapy toxicity. [6]  The CARG tool was derived from a study of 500 patients undergoing a variety of chemotherapy regimens for various solid tumors. The CARG tool was recently validated externally [11] and helps to identify patients at greatest risk of chemotherapy toxicity.  Although the CARG tool has been proven in a mixed cohort of patients with various cancers, there are no validation data for patients with mCRPC, and only 10% of the patients in the original study had genitourinary cancers. [6]  Since different chemotherapy regimens have different toxicity risks, it is important to validate such tools in a more homogeneous cohort to ensure findings are similar to mixed cohorts. 

    Oncologist Judgment

    For our study, we had each patient’s medical oncologist rate the patient’s risk of chemotherapy toxicity on a 10-point scale.  “Oncologists are left with little guidance when it comes to identifying risk factors other than chronologic age or performance status, neither of which has been shown to predict well in heterogeneous older adult populations.” [6] 

    Methods

    We recruited men aged 65 or older with mCRPC who were starting either first-line chemotherapy (receiving chemotherapy for the first time) or second-line chemotherapy (stopped first-line chemotherapy because of disease progression, toxicity, or other reasons).  All but two (4%) participants received docetaxel-based chemotherapy, and the majority (n=29, 63%) received the standard dose of 75 mg/m2 every 3 weeks.  Ten (22%) received a dose of 60 mg/m2, whereas 5 (11%) received a lower dose than this.  Subjects were recruited either prior to starting chemotherapy or within the first two cycles as long as there was no dose reduction.  Men unable to come for study visits or with a life expectancy of less than 3 months, a major neuropsychiatric abnormality, or limited English were excluded from the study.

    We collected socio-demographic and medical information on all subjects at baseline, as well as physical performance measures (grip strength, timed up and go, and timed chair stands).  The CARG and VES-13 tools were administered as well.  The CARG toxicity prediction model was used to stratify patients into three groups (low, intermediate, and high risk) based on risk for grade 3+ chemotherapy toxicity.  The VES-13 was used to measure vulnerability, which was defined by a score of 3 or greater.  This cut-off point follows the conventional scoring system, but we also examined cut-offs of 2 or greater and 4 or greater.  We also asked each subject’s treating physician to provide an estimate of the risk of chemotherapy toxicity on a scale from 1 (lowest risk) to 10 (highest risk).  Oncologists were not told the results of the other assessment tools used in the study. 

    Following the baseline visit, follow-up assessments were performed after each cycle of chemotherapy (every 3 weeks) and after the final cycle.  At each visit, a trained research coordinator recorded chemotherapy-related toxicities using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4).  Laboratory-based toxicities such as neutropenia were based on blood tests performed every three weeks.  These same procedures were followed to record toxicity for men who were recruited after already having started chemotherapy, including for cycles administered before being enrolled on the study.

    Sample sizes were based on the assumption that we would see the same rate of toxicity as in the original CARG study (i.e. 30% risk of grade 3+ toxicity for the low risk group, 52% for intermediate, and 83% for high) [6] and that equal proportions of patients would be enrolled in each risk group (i.e. one-third for each).  Based on these assumptions, we calculated that we would require 45 patients. 

    Results

    46 men were recruited for the study with a mean age of 75.  These participants had a median PSA level at baseline of 243.7 ng/mL and had relatively few other major medical problems (median Charlson Comorbidity Index score of 0).  Although participants had a fairly high performance status (mean Karnofsky score of 77%), 50% were considered vulnerable based on the VES-13.  Based on the CARG tool, only 2 (4%) patients were considered low risk, 29 (63%) were intermediate, and 15 (33%) were high risk of severe chemotherapy toxicity. 

    Grade 3+ and grade 2 chemotherapy toxicity were experienced by 20% and 67% of patients, respectively.  The most common grade 3-5 toxicities were neutropenia (30%), generalized weakness (23%), and bone pain (15%), and the most common grade 2 toxicities were fatigue (35%), peripheral edema (7%), and mucositis (7%).

    Grade 3+ toxicity was observed in 0 (0%), 5 (17%) and 4 (27%) patients in low, intermediate, and high CARG risk groups respectively, suggesting an incremental pattern across risk groups.  However, this pattern was not statistically significant (p = 0.65).  22% of patients considered vulnerable by the VES-13 experienced grade 3+ toxicity, compared to 17% of patients considered non-vulnerable (p = 0.71).  Age, comorbidity, Karnofsky performance score, and baseline physical performance measures did not seem to be predictors of grade 3+ toxicity.  In addition, oncologist judgment of toxicity risk was a relatively poor predictor of actual toxicity.

    The ability of the CARG tool to predict grade 2 toxicity appeared to be higher than the ability of the VES-13 to predict these toxicities, but this was not statistically significant, likely due to our small sample size (p = 0.072 for CARG, 0.75 for VES-13).  Limiting the analyses to only those participants who were recruited prior to starting chemotherapy did not alter the findings.

    The rates of grade 3+ toxicity found in our cohort were relatively low overall: only 20% compared to the 53% observed in the original CARG study.  The same pattern was found in the three individual risk groups, with lower rates of toxicities observed in each compared to the original CARG study.  However, the rate of toxicity in our cohort was similar to rates reported in other studies of older men with mCRPC.  For example, the TAX327 trial by Tannock et al. reported severe adverse events in 26% of subjects, and grade 3+ neutropenia in 32%. [5]

    Although we did not find statistically significant results for either of the tools tested, we did observe three key findings in our study.  First, the risk of grade 3+ toxicity with docetaxel-based chemotherapy in the mCRPC population is lower overall and across CARG risk groups compared to the rates observed in the original study, which used data from patients with a variety of cancers.  However, we still found that there was a gradient of toxicity risk across the different CARG risk groups (i.e. 0% in low, 17% in moderate, and 27% in the high risk group).  Therefore, there is a need for further validation studies conducted with older men with mCRPC.

    Second, our data on the performance of the VES-13 are the first in this population.  Even though our findings were negative, we believe they warrant further investigation because of the ease of use and emerging value of the VES-13 in other geriatric oncology settings (e.g. 12).  Third, we also provided the first data looking at oncologist judgment of toxicity risk, and compared that to the CARG and VES-13 tools.  For tools to be useful in a busy clinical setting, they must provide better predictive ability than the usual clinical care.  Therefore, further investigation in this area is important.

    Some other limitations include the fact that we conducted our study at a single academic cancer center, limiting generalizability, and did not use the CRASH tool, another popular tool for predicting toxicities. [13]  Future studies should directly compare the CRASH and CARG tools in the mCRPC setting.  Lastly, the 10-point rating scale we used for oncologist predictions has not been validated in this context, and we did not provide any numerical anchors.  Therefore, the different ratings may have meant different things to different oncologists.  Further investigation is warranted in these areas.

    Conclusion

    In summary, toxicity with docetaxel in a cohort of older men in usual clinical practice was lower than predicted by the CARG tool.  Although the CARG tool appeared to differentiate those at lower versus higher risk of chemotherapy toxicity and was better than clinician judgement or ECOG PS, a larger validation study is needed.

    Written By: Thavalis Ja, Rathore Ma, Breunis Ha, Alibhai SMHa,b,c
    a. Department of Medicine, University Health Network 

    b. Department of Medicine, University of Toronto 
    c. Institute of Health Policy, Management and Evaluation, University of Toronto 

    References 

    1. American Cancer Society. Key statistics for prostate cancer [Internet]. American Cancer Society Inc.; 2016 [updated 2017 Jan 5]. Available from https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html 
    2. Nussbaum N, George DJ, Abernethy AP, Dolan CM, Oestreicher N, Flanders S, Dorff TB. Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science. Prostate Cancer and Prostatic Diseases. 2016 Jun 1;19(2):111-21. 
    3. American Cancer Society. Prostate cancers [Internet]. American Cancer Society Inc.; 2016 [updated 2016 Mar 11]. Available from https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html 
    4. Chi K, Hotte SJ, Joshua AM, North S, Wyatt AW, Collins LL, Saad F. Treatment of mCRPC in the AR-axis-targeted therapy-resistant state. Annals of Oncology. 2015 Oct 1; 26(10):2044-56.
    5. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. New England Journal of Medicine. 2004 Oct 7; 351(15):1502-12.
    6. Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, Lichtman SM, Gajra A, Bhatia S, Katheria V, Klapper S. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. Journal of Clinical Oncology. 2011 Aug 1; 29(25):3457-65.
    7. Rose JH, O'Toole EE, Dawson NV, Lawrence R, Gurley D, Thomas C, Hamel MB, Cohen HJ. Perspectives, preferences, care practices, and outcomes among older and middle-aged patients with late-stage cancer. Journal of Clinical Oncology. 2004 Dec 15; 22(24):4907-17. 
    8. Kelly CM, Shahrokni A. Moving beyond Karnofsky and ECOG performance status assessments with new technologies. Journal of Oncology. 2016 Mar 15; 6186543.
    9. Sørensen JB, Klee M, Palshof T, Hansen HH. Performance status assessment in cancer patients. An inter-observer variability study. British Journal of Cancer. 1993 Apr; 67(4):773-5.
    10. Saliba D, Elliott M, Rubenstein LZ, Solomon DH, Young RT, Kamberg CJ, Roth C, MacLean CH, Shekelle PG, Sloss EM, Wenger NS. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. Journal of the American Geriatrics Society. 2001 Dec 1; 49(12):1691-9.
    11. Hurria A, Mohile S, Gajra A, Klepin H, Muss H, Chapman A, et al.  Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults With Cancer.  Journal of Clinical Oncology. 2016 Jul 10; 34(20:2366-71.
    12. Luciani A, Ascione G, Bertuzzi C, Marussi D, Codeca C, Di Maria G, et al.  Detecting disabilities in older patients with cancer: comparison between comprehensive geriatric assessment and vulnerable elders survey-13.  Journal of Clinical Oncology. 2010 Apr 20; 28(12):2046-50.
    13. Extermann M, Boler I, Reich RR, Lyman GH, Brown RH, DeFelice J, et al. Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2011 Nov 9; 118(13):3377-86.
    Read the Abstract
    Published June 1, 2017
  • CUA 2017: Fatigue in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Enzalutamide: Data from Randomized Clinical Trials.

    Toronto, Ontario (UroToday.com) Enzalutamide (Enza) is a novel androgen inhibitor with established efficacy in metastatic castration-resistant prostate cancer (CRPC). The AFFIRM and PREVAIL trials established its efficacy in the post-chemotherapy and pre-chemotherapy phases (***). Along with abiraterone (Abi), it is one of two approved oral agents for this disease state. However, the decision to utilize one over the other is often determined by adverse event profiles and contraindications. 
    Published June 26, 2017

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