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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 GU 2019: Final Analysis of LATITUDE, A Phase III in Patients with Newly Diagnosed High-risk Metastatic Castration-naïve Prostate Cancer

    San Francisco, CA (UroToday.com) The LATITUDE study,1 published in July 2017, was a phase III randomized, clinical trial that evaluated the efficacy of abiraterone acetate and prednisone with androgen deprivation therapy (ADT) in men with newly-diagnosed, castration sensitive, metastatic prostate cancer. 1199 men were randomized to receive ADT with abiraterone and prednisone, versus ADT with dual placebos. The primary endpoints of this study were overall survival and radiographic progression-free survival. This study showed that ADT+ abiraterone and prednisone conferred a survival benefit over ADT alone, but also showed that there was an improvement in patient-reported outcomes (PROs) over the course of the trial.
    Published February 15, 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 2018: Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018

    San Francisco, CA (UroToday.com) David F. Jarrard, MD provided an update on the CRPC AUA guideline amendment at 113th Annual Scientific Meeting of the American Urological Association (AUA). Dr. Jarrard highlights, the six index patients associated with the CRPC guidelines assists in clinical decision making, representing the most common clinical scenarios that are encountered in clinical practice. Guideline statements are developed to provide a rational basis for treatment based on currently available published data. The purpose of this guideline amendment is essentially to update current management of index patient 1: asymptomatic non-metastatic CRPC (nmCRPC).
    Published May 21, 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
  • Chemotherapy in Prostate Cancer- When, Why and How

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 4
    Until 2010, our treatment armamentarium for prostate cancer (PC) was fairly limited. Patients received local therapy for non-metastatic disease, androgen deprivation therapy (ADT) for hormone-naïve metastatic disease, denosumab and zoledronic acid for metastatic castration-resistant prostate cancer (mCRPC), and bisphosphonates or docetaxel for symptomatic mCRPC.
    Published February 28, 2018
  • EAU 2019: Conclusions from Recent Oncology Meetings Regarding: Castration-Resistant Prostate Cancer

    Barcelona, Spain (UroToday.com) In this session, Dr. Evans presented a review of some of the most important studies in the castrate-resistant prostate cancer space published in the past year. First, from ESMO 2018, in a phase 3 randomized controlled trial, radium 223 with abiraterone (ERA 223) did not demonstrate improved symptomatic skeletal-related event-free or overall survival compared to abiraterone with placebo. Clinical fractures were more common in the abiraterone and radium group. Based on the data from the study, the use of radium 223 in combination with abiraterone was not recommended.
    Published March 19, 2019
  • EAU 2019: PROpel: Olaparib Combined with Abiraterone as First-Line Therapy In mCRPC

    Barcelona, Spain (UroToday.com) PARP inhibitors have been increasingly recognized for their potential therapeutic role in patients with advanced prostate cancer, particularly in the setting of DNA repair defects. Prior work by Dr. Clarke and colleagues demonstrated, in a phase II clinical trial (NCT01972217), that olaparib (given as tablets, 300 mg bid) in combination with abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) significantly prolonged radiologic progression-free survival (rPFS) compared with abiraterone alone (median 13.8 vs 8.2 months; HR 0.65, 95% CI 0.44–0.97, P=0.034) in patients with mCRPC in the second-line metastatic setting who received prior docetaxel1. Building on this, the authors are now taking this to a randomized phase III multi-institution international clinical trial – but as a first-line therapy for patients with mCRPC.
    Published March 19, 2019
  • EAU 2019: The Advances in the Treatment of Castrate Resistant Prostate Cancer

    Barcelona, Spain (UroToday.com) Dr. Robert Van Soest presented on the recent advances in the treatment of castrate-resistant prostate cancer (CRPC). The current therapeutic options in metastatic hormone-sensitive prostate cancer (mHSPC), and the 1st and 2nd treatment lines of metastatic CRPC are shown in Figure 1.
    Published March 21, 2019
  • EAU PCa 17: Castration resistant prostate cancer: Drug selection and treatment sequencing

    Vienna, Austria (UroToday.com) Dr. Bertrand Tombal from Belgium provided a discussion during the General Updates on Systemic Treatments at the EAU Update on Prostate Cancer, focusing on drug selection and treatment sequencing among men with castration resistant prostate cancer (CRPC). As Dr. Tombal notes, the drug portfolio for men with CRPC in 2017 is quite vast, including docetaxel, abiraterone (pre/post docetaxel), enzalutamide (pre/post docetaxel), cabazitaxel (post-docetaxel), Sipuleucel-T (pre-docetaxel), and radium-223 (post-docetaxel or in docetaxel unfit).
    Published September 18, 2017
  • EAU PCa 17: Hormone-naïve metastatic disease: How to treat it?

    Vienna, Austria (UroToday.com) Dr. Axel Merseburger from Germany started the session on General Updates on Systemic Treatments at the EAU Update on Prostate Cancer discussing how best to treat patients with hormone-naïve metastatic prostate cancer (mHNPC). 
    Published September 22, 2017
  • Embarrassment of Riches: Therapies that Improve Overall Survival in mCRPC

    Published in Everyday Urology - Oncology Insights: Volume 1, Issue 1
    Before 2004, there was an unmet need for survival prolonging therapies in men with castration-resistant prostate cancer (CRPC). Palliative therapeutic options were the standard of care. As a result, there was a pervasive nihilism regarding the therapeutic management of men with advanced prostate cancer, especially after they ceased responding to androgen suppressive therapy.
    Published October 4, 2016
  • European Commission Approves Abiraterone Acetate + Prednisone for Early Stage Prostate Cancer

    Truckee, CA (UroToday.com) Janssen-Cilag International NV (Janssen) announced that the European Commission (EC) has granted approval to broaden the existing marketing authorisation for ZYTIGA® (abiraterone acetate) plus prednisone / prednisolone to include an earlier stage of metastatic prostate cancer than its current indications. Abiraterone acetate plus prednisone / prednisolone can now be used for the treatment of newly-diagnosed high-risk metastatic hormone-sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT).1 
    “Prostate cancer is the most common form of cancer in men throughout Europe and today’s decision helps to fill a critical medical need for these patients. We hope to significantly improve the lives of many men across Europe living with this disease and the approval of this treatment in an earlier stage of prostate cancer helps address this,” said Professor Karim Fizazi, principal investigator of the LATITUDE trial and Head of the Medical Oncology Department at Institute Gustave Roussy, France. 
    The EC’s decision follows a recommendation from the Committee for Medical Products for Human Use (CHMP)2 that was based on data from the multinational, multicentre, randomised, double-blind, placebo-controlled Phase 3 study, LATITUDE. The trial was designed to determine if newly diagnosed patients with metastatic prostate cancer, who are naïve to castration and have high-risk prognostic factors, would benefit from the addition of abiraterone acetate and prednisone to androgen deprivation therapy (ADT) vs ADT alone.3 Data were presented at the 2017 American Society of Clinical Oncology congress in Chicago, USA and published in the New England Journal of Medicine. 
    “This EC approval is a major step forward for men living with prostate cancer across Europe and offers patients with newly diagnosed high-risk metastatic hormone-sensitive prostate cancer a new treatment option. We are encouraged by the data we have seen to date and remain committed to transforming outcomes for prostate cancer patients,” said Dr. Ivo Winiger-Candolfi, Oncology Solid Tumor Therapy Area Lead, Janssen Europe, Middle East and Africa. 
    Abiraterone acetate plus prednisone / prednisolone has already been approved by the European Commission (EC) for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in adult men who are asymptomatic or mildly symptomatic after failure of ADT in whom chemotherapy is not yet clinically indicated and in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.4 

    In the LATITUDE study, the safety profile of ADT in combination with abiraterone acetate plus prednisone was consistent with prior studies in patients with mCRPC. Most common adverse events were elevated incidences of mineralocorticoid-related hypertension and hypokalemia in the ADT in combination with abiraterone acetate plus prednisone arm compared with ADT and placebos.3 The observed degrees of hypertension and hypokalemia were both medically manageable. They only rarely required treatment discontinuation and seldom led to serious consequences.3 

    References
    1 EC website. Community register of medicinal products for human use. ZYTIGA product information. 
    2 European Medicines Agency. ZYTIGA CHMP meeting highlights. 
    3 Fizazi, K. et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. New England Journal of Medicine 2017; 377:352-360.
    4 ZYTIGA® summary of product characteristics (February 2017). 

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    Published November 20, 2017
  • Local Cancer Survivor and Entrepreneur Donates $500,000 to Fund UMN Cancer Research Initiative

    San Francisco, CA USA (UroToday.com) --  Cancer mortality is higher among men than it is among women. It’s estimated that more than 174,000 new cases of prostate cancer, which is the most common cancer in American men, will be diagnosed in 2019 according to the American Cancer Society. Survival rates are improving as new cancer treatments are developed and become more effective.
    Published January 24, 2019
  • Low Incidence of Corticosteroid-associated Adverse Events on Long-term Exposure to Low-dose Prednisone Given with Abiraterone Acetate to Patients with Metastatic Castration-resistant Prostate Cancer.

    Abiraterone acetate (AA) is the prodrug of abiraterone, which inhibits CYP17A1 and testosterone synthesis and prolongs the survival of patients with metastatic castration-resistant prostate cancer (mCRPC).

    Published March 13, 2016
  • MDACC 2018: Local Therapy in Metastatic Prostate Cancer

    Houston, Texas (UroToday.com) The rationale for definitive treatment of the primary tumor in metastatic prostate cancer includes retrospective data suggesting improvement in overall survival, reduction of local symptomatic progression, the systemic biology may be altered, there may be molecularly lethal prostate cancer that persists in the primary and finally, a randomized trial is feasible and local treatment is safe.
    Published November 11, 2018
  • Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer.

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

    Published March 13, 2016
  • Sequencing and Combining CRPC Therapies - What Does the Future Hold?

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 4
    The European Association of Urology defines castration-resistant prostate cancer (CRPC) as serum testosterone < 50 ng/dL or < 1.7 nmol/L plus either biochemical progression (three consecutive rises in prostate-specific antigen [PSA] one week apart, resulting in two 50% increases over the nadir, and PSA > 2 ng/mL) or radiologic progression
    Published February 28, 2018
  • The Five-Take Home Messages of the LATITUDE and STAMPEDE Studies

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 3
    LATITUDE was a phase III trial of men with high-volume metastatic prostate cancer (PC) that had not been previously treated with androgen deprivation therapy (ADT).1 The patients were randomized to receive standard ADT with placebos vs. ADT plus abiraterone and prednisone. The primary endpoint is overall survival (OS).
    Published November 22, 2017
  • The Impact of Visceral Metastasis in Prostate Cancer Patients

    Introduction and Epidemiology

    In 2018 in the United States, there will be an estimated 164,690 new cases of prostate cancer (19% of all male cancer incident cases, 1st) and an estimated 29,430 prostate cancer mortalities (9% of all male cancer deaths, 2nd only to lung/bronchus cancer).1 For the last 30 or more years, prostate cancer has been the most common noncutaneous malignancy among men in the United States, with 1 in 7 men being diagnosed with the disease.2 De-novo metastatic prostate cancer incidence seems to vary by geographical region and ranges from 4.4 to 9.9 per 100,000 men. A recent study found that over the last several decades, the incidence of de novo metastatic prostate cancer was decreasing in the United States (12.0 to 4.4 per 100,000 men) but increasing in Denmark (6.7 to 9.9 per 100,000 men).3 The exact mechanism for these epidemiologic differences is not clear, but likely related to varying uptake and utilization of PSA surveillance.

    With improvements in the treatment of advanced prostate cancer over the last decade, men with advanced disease are living longer and developing non-lymph node visceral metastases.  In a single-institution Japanese study (from 2000-2014), among 1,038 prostate cancer patients, there were 144 (19.8 %) men with castration-resistant prostate cancer (CRPC) and 43 (33.1%) patients developing visceral metastases after CRPC progression.4 At diagnosis, the sites of visceral metastases included lung (89.5%), liver (5.3%), and adrenal glands (5.3%). After CRPC progression, new visceral metastases were found in the lung (47.3%), liver (43.6%), and adrenal gland (9.1%). Among 359 CRPC patients in the UK (June 2003 to December 2011), the frequency of radiologically detected visceral metastases before death was 32%; among the 92 patients with a CT scan performed within 3 months of death, 49% had visceral metastases, most commonly involving the liver (20%) and lung (13%).5 These findings confirm a large autopsy study that found among 1,500 prostate cancer patients, 25% of men had liver metastases and 46% had lung metastases.6 Of men participating in first-line studies for metastatic CRPC (mCRPC), ~20% of patients had non-lymph node soft tissue visceral metastases.7,8 As such, leaders in the field have suggested that men with visceral metastases have been an underestimated and understudied subgroup of patients with advanced and heavily treated mCRPC.9,10 The objective of this article is to discuss the biology of visceral metastases, assess the impact of visceral metastases on survival, highlight several large trials that have performed subgroup analyses of visceral metastases patients, and discuss emerging therapeutic regimens for these patients, specifically radioligand targeted therapy.

    The Biology of Visceral Metastases

    We are likely only beginning to understand the biology of visceral metastases, particularly as it differs from that of bone metastases. There are several interrelated factors leading to differing pathophysiology between visceral and bone metastases, namely intrinsic cellular factors, the tumor microenvironment, and systemic factors.

    1. Cellular Factors: Immunohistochemical analysis of tissue microarrays examining the antiapoptotic pathways expressed in visceral vs bone metastases found that soft-tissue metastases are more likely to express nuclear survivin, whereas bone lesions demonstrate relative overexpression of cytoplasmic survivin, B-cell lymphoma 2, and myeloid cell leukemia 1.11
    2. Tumor Microenvironment: microarray studies have found physiologically and clinically important differences between bone, liver, and lymph node metastases. Visceral lesions derived from liver and lymph nodes were found to express an angiogenic profile different from that of liver metastases alone, with significant relative overexpression of the proangiogenic factor angiopoietin-2.12
    3. Systemic Factors: serum cytokine levels are associated with prognosis as well as with the presence of liver metastases among prostate cancer patients.9,13 A number of studies have examined levels of TGF-β and interleukin-6 (IL-6) as prognostic markers, finding that the addition of TGF-β and soluble IL-6 receptor levels to a preoperative nomogram significantly improved the ability to predict biochemical progression of the disease.14

    Impact of Visceral Metastases on Survival

    Patients with visceral metastases invariably have a worse prognosis than patients with bone-only metastases, likely secondary to an overall increased disease burden.5,10,15-26 In a study including patients in the SEER database (2010-2013), patients with de-novo bone-metastases plus visceral metastases had significantly worse prostate cancer-specific mortality (vs bone only): bone + brain metastases HR 1.48, 95%CI 1.05-2.10; bone + liver metastases HR 2.18, 95%CI 1.79-2.65; bone + lung metastases HR 1.33, 95%CI 1.13-1.56.27

    Several large phase III randomized controlled trials (RCTs) have assessed the impact of visceral metastases on survival outcomes using post-hoc analysis of the trial data. The TAX 327 trial found that docetaxel plus prednisone improved OS, pain scores, PSA level, and quality of life compared to mitoxantrone plus prednisone among patients with mCRPC.8 A decade after this publication, Pond et al.25 performed a post-hoc analysis of this data stratified by metastasis site. They found that men with liver metastases with or without other metastases had a shorter median OS (10.0 months; 95%CI 5.4-11.5) than men with lung metastases with or without bone or nodal metastases (median OS: 14.4 months; 95%CI 11.5-22.4). The AFFIRM trial showed that treatment with the androgen receptor inhibitor enzalutamide led to significant improvements in outcomes for patients with mCRPC.28 A subsequent study assessed patients in the AFFIRM trial who had liver and/or lung metastases.20 In patients with liver metastases (n = 92), enzalutamide treatment was associated with a lower risk of radiographic progression (HR 0.645, 95%CI 0.413-1.008), improved 12-month OS (37.7% vs 20.6%) and radiographic progression-free survival (rPFS) (11.6% vs 3.0%) rates compared to those on placebo. Furthermore, patients treated with enzalutamide had higher PSA response rates (35.1% vs 4.8%) compared with placebo. Similarly, patients with lung metastases (n = 104) treated with enzalutamide also had an improved median OS (HR 0.848, 95%CI 0.510-1.410), reduced risk of radiographic progression (HR, 0.386, 95%CI 0.259-0.577), improved 12-month OS (65.1% vs 55.3%) and rPFS (30.9% vs 8.2%) rates, and a better PSA response rate (52.1% vs 4.9%) compared with those who received placebo. The PREVAIL clinical trial tested enzalutamide in men with mCRPC prior to chemotherapy, finding a decreased risk of radiographic progression and death among those taking enzalutamide compared to placebo.29 Of the 1,717 patients in PREVAIL, 12% had visceral metastases: 74 with liver-only or liver/lung metastases and 130 with lung only metastases.19 In patients with liver metastases, treatment with enzalutamide was associated with an improvement in rPFS (HR 0.44, 95%CI 0.22-0.90) but not OS. Among patients with lung metastases only, enzalutamide significantly improved rPFS (HR 0.14, 95%CI 0.06-0.36) and OS (HR 0.59, 95%CI 0.33-1.06). Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment.

    Results of post-hoc analyses of phase III RCTs showing poor outcomes among patients with visceral metastases have also been confirmed using population-level studies. Gandaglia et al.24 utilized the SEER-Medicare database (1991-2009) to assess outcomes of 3,857 patients presenting with metastatic prostate cancer. Among these patients, 80.2% had bone metastases, 10.9% had bone plus visceral metastases, 6.1% had visceral only metastases, and 2.8% had lymph node only metastases. Patients with bone plus visceral metastases had the worst cancer-specific survival (median 19 months), following by visceral only metastases (median 26 months), bone-only metastases (median 32 months) and lymph node only metastases (median 61 months). Patients with visceral metastases had a significantly higher risk of overall and cancer-specific mortality compared to those with exclusively lymph node metastases (p<0.001), and the unfavorable impact of visceral metastases persisted in the oligometastatic subgroup. Whitney et al.18 studied 494 men with M0 CRPC (diagnosed after 1999) from five Veterans Affairs hospitals in the Shared Equal Access Regional Cancer Hospital (SEARCH) database who later developed metastases. Among these patients, 236 men had a CT scan performed, of which 38 (16%) had visceral metastases, including 19 patients with liver metastases, 8 patients with lung metastases, and 16 patients with other locations of metastases. The authors found that visceral metastases were a predictor of OS on univariate analysis and after risk adjustment (HR 1.84, 95%CI 1.24-2.72).

    To further assess the impact of metastatic site on OS among men with mCRPC, a collaborative group performed an individual patient data meta-analysis of 8,820 men with mCRPC who received docetaxel chemotherapy in nine phase III RCTs.22 Site of metastases was categorized as lymph node only, bone with or without lymph node involvement (with no visceral metastases), and lung metastases (but no liver), and any liver metastases. 72.8% of patients had a bone with or without lymph node metastases, 20.8% had a visceral disease, and 6.4% had lymph node-only disease. Men with lymph node-only disease had the best survival with a median OS of 31.6 months, followed by men with non-visceral bone metastases (median OS 21.3 months), men lung metastases (median OS 19.4 months), and those with liver metastases (median OS 13.5 months).

    There are several take-home messages from these studies assessing survival outcomes among patients with visceral metastases:

    1. Patients with any degree of liver metastases typically have the worst survival outcomes compared to those with bone metastases or other sites of visceral metastases
    2. Patients with visceral metastases do have a response to enzalutamide (either in the pre- or post-chemotherapy setting), although their prognosis remains poor

    Radioligand Therapy for mCRPC Patients

    The recent uptake in the utilization of PSMA-PET/CT imaging has led to a new field of therapy among heavily pretreated mCRPC patients: radioligand directed therapy. The high PSMA expression in prostate cancer metastases makes it a promising approach to developing new tracers for targeted radionuclide therapies. Since 2015, several institutional studies have reported promising results for response rates and a favorable safety profile after radioligand therapy with 177Lu-PSMA-617 in patients with mCRPC,30-34, however, these studies have suffered from small sample sizes and thus poor generalizability. In an effort to overcome these issues, Rahbar and colleagues35 performed a multicenter German analysis among a cohort of patients treated with 177Lu-PSMA-617.  There were 145 patients with mCRPC treated with 177Lu-PSMA-617 at 12 centers undergoing 1-4 therapy cycles with an activity range of 2-8 GBq per cycle. Among these patients, 87% had bone, 77% lymph node, 20% liver, 14% lung, and 2% other sites of metastases. The study reported an overall biochemical response rate of 45% after all therapy cycles, including 40% of patients who responded after a single cycle. Notably, negative predictors of biochemical response include elevated alkaline phosphatase and the presence of visceral metastases.

    A study published last month reported on 100 consecutive patients at a single institution receiving 177Lu-PSMA-I&T, treated with a median of two cycles of therapy (range 1-6).36 Among these 100 patients, 57 had received ≥3 prior treatment regimens for mCRPC. There were 87 patients that had lymph metastases and 35 with visceral metastases, including 18 with liver, 11 with lung and 8 with adrenal metastases. A PSA decline of ≥50% was achieved in 38 patients, the median clinical progression-free survival was 4.1 months, and median OS was 12.9 months.  The presence of visceral metastasis was the only variable associated with a poor PSA response (p = 0.049), as only nine of 35 (26%) patients with visceral metastasis achieved a maximum PSA decline of ≥50%. The authors concluded that the presence of visceral metastases and rising LDH were associated with worse treatment outcome.

    Although 177Lu-PSMA-617 is the most well-studied radioligand to date, there are several other compounds in development and undergoing initial testing. These compounds include: 177Lu-J591, 90Y-J591, 131I-MIP 1095, 177Lu-PSMA-I&T, and 225Ac-PSMA-617.37

    Conclusions  

    Secondary to the improved treatment options available for patients with mCRPC, these men are living longer and thus increasing the prevalence of mCRPC patients with visceral metastases. Although post-hoc studies of enzalutamide trials in the pre- and post-chemotherapy mCRPC setting demonstrate a degree of response, visceral metastases are associated with poor survival outcomes. Initial radioligand therapy studies, primarily with 177Lu-PSMA-617, show promise for heavily treated mCRPC patients, although subgroup analyses of these studies also demonstrate worse survival among patients with visceral metastases. For the future design of phase II and phase III clinical trials among men with mCRPC, patients should be stratified by metastasis site to preclude patients with visceral metastases being inadvertently randomized to an unbalanced trial arm. Further efficacious treatment options for these patients are in dire need. The treatment of visceral metastases is one of the new therapeutic frontiers for prolonging not only quantity but also the quality of life.

    Written by: Zachary Klaassen, MD
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    Published April 16, 2019
  • The Importance of Clinical Trials for Genitourinary Malignancies

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 4
    As we counsel our patients about the importance of clinical research, there are two key messages to send. The first is that without clinical trials, we would not have access to the large number of life-prolonging therapies that we have for genitourinary cancers and others. That translates into more family trips, birthday parties, time spent with grandchildren and graduations attended.
    Published February 28, 2018
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