Evolving Paradigm of Metastatic Prostate Cancer Management: Timely Identification and Intervention

Urology Practice Management Special Issue - September 2013 Vol 2, No 3 published on October 15, 2013
John A Welz, MPH
Gary Kirsh, MD
Lisa A. Raedler, PhD, RPh

For men in the United States, prostate cancer is the most commonly diagnosed solid tumor malignancy. It is one of the highest cancer-specific causes of death, second only to lung cancer.1

At the time of diagnosis with prostate cancer, most men have early-stage, asymptomatic disease. Prostate cancer is typically identified through prostate-specific antigen (PSA) testing and a digital rectal examination, and confirmed with a  needle biopsy. When biopsy results are positive, the affected tissue is assessed microscopically and a Gleason score is calculated. In conjunction with other disease features and diagnostic test results, this score helps urologists determine the disease stage and prognosis, and facilitates the selection of initial therapy.2 Active surveillance, external radiation therapy, brachytherapy, radical prostatectomy, and androgen deprivation therapy (ADT) are relevant treatment options for men in the early stages of prostate cancer. Treatment selection is influenced by the risk of disease recurrence, the patient’s life expectancy, and quality-of-life considerations.3

Even with treatment, prostate cancer often progresses. Among patients with biochemical recurrence of localized disease, more than one third (33%) of men who are treated with surgery or radiation are not cured. In men who are treated with ADT, nearly all will go on to develop castration-resistant prostate cancer (CRPC). CRPC is characterized by a rising PSA level despite a castrate testosterone level of <50 ng/dL.3-6 More than 80% of patients with CRPC will advance and develop metastases.5 Progression to metastatic disease (mCRPC) is frequently rapid, with 46% of men with CRPC developing metastases within 2 years. Even patients with a low PSA level or longer PSA doubling time are at significant risk for metastatic disease.6

In addition to the men who progress to mCRPC, approximately 5% of men with prostate cancer are newly diagnosed with metastatic disease.7 Because the 5-year relative survival rate at diagnosis is only 28% for these men, mCRPC treatment tends to be relatively aggressive and generally involves ADT. Various agents are characterized as ADT, including luteinizing hormone-releasing hormone agonists such as Lupron (leuprolide acetate) and antiandrogen agents, such as Nilandron (nilutamide), Casodex (bicalutamide), and Eulexin (fluta­mide). While ADT is a mainstay of prostate cancer treatment, these agents are associated with various side effects, including hot flashes and flushing; bone demineralization, which can lead to osteoporosis; and central weight gain and insulin resistance, which can contribute to the onset of diabetes and cardiovascular disease.3 Urologists monitor patients who use ADT for these toxicities, and frequently offer nutritional and cardiovascular care to mitigate long-term complications.

In the past, most men with mCRPC received cytotoxic chemotherapy. However, the treatment landscape has changed in recent years with the approval of several novel therapies (Table 1).3

Table 1

Provenge (sipuleucel-T) was approved by the US Food and Drug Administration (FDA) in 2010 for asymptomatic or minimally symptomatic mCRPC. Sipuleucel-T is an autologous cellular immunotherapeutic agent that is typically administered in 3 doses at approximately 2-week intervals for 4 weeks. In the prechemotherapy setting, sipuleucel-T is the only anticancer agent that has demonstrated statistically significant improvement in overall survival (OS). In a clinical study, sipuleucel-T extended OS in patients with mCRPC by 25.8 months (vs 21.7 months for controls), conferring an OS advantage of 4.1 months.8 Data suggest that an optimal treatment window may exist for sipuleucel-T. In a subgroup analysis of clinical trial data, sipuleucel-T was shown to work better in men with lower PSA scores, extending OS up to 41.3 months (Table 2).9

Table 2

The most common adverse events (AEs) reported in trials of sipuleucel-T were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Serious AEs included acute infusion reactions, cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.8

Zytiga (abiraterone acetate), an oral agent given once daily with prednisone, was initially approved by the FDA in 2011 for patients with mCRPC after cytotoxic chemotherapy. In the postchemotherapy setting, the phase 3 trial demonstrated that abiraterone improved OS by a median of 3.9 months in the primary survival analysis, and 4.6 months in an updated OS analysis. Zytiga has also been studied in the prechemotherapy setting. Researchers selected 2 primary end points, radiographic progression-free survival (rPFS) and OS.  At the prespecified analysis of rPFS, 72% of patients had neither experienced radiographic progression nor died while receiving abiraterone versus 54% receiving placebo. The median time to initiation of cytotoxic chemotherapy was 25.2 months with abiraterone versus 16.8 months with placebo. This difference between the treatment groups was statistically significant. The findings were less compelling in terms of OS. Although OS was longer with Zytiga than with placebo (hazard ratio = 0.792), the P value was .015, which did not meet the prespecified value for statistical significance. Abiraterone received approval for patients with mCRPC prior to chemotherapy in December 2012.10
Side effects of abiraterone can include fluid retention, which can cause an increase in blood pressure, and, occasionally, lowering of potassium levels and elevation of liver functions. Liver function tests are recommended for patients receiving abiraterone.10

Another oral agent, Xtandi (enza­lutamide), was approved in August 2012 as monotherapy for patients with mCRPC who have previously received docetaxel. Enzalutamide is given once daily, and in a phase 3, placebo-controlled, randomized clinical trial of patients with mCRPC who previously received docetaxel, OS was extended by 18.4 months versus 13.6 months in patients receiving placebo, for an OS advantage of 4.8 months. Common side effects include fatigue, diarrhea, hot flushes, and headache. In a pivotal phase 3 clinical trial, 7 patients receiving enzalutamide reported seizures versus no patients in the placebo group.11

In May 2013, the FDA approved Xofigo (radium Ra 223 dichloride), the first alpha particle-emitting radioactive therapeutic agent for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastatic disease.  In these patients, radium 223 combined with best standard of care demonstrated a significant 3.6-month improvement in median OS compared with placebo plus best standard of care. This OS improvement was supported by a delay in time to the first symptomatic skeletal-related event favoring the radium 223 arm. Radium 223 is not approved for use in combination with docetaxel or any other chemotherapy agent.3,12

Sequential or concurrent treatment of patients with mCRPC with newer agents is being explored in clinical trials. In a randomized, phase 2 open-­label study, researchers are evaluating concurrent or sequential abir­aterone acetate plus prednisone to determine whether increased suppression of the androgen axis with abir­aterone acetate could provide synergy when combined with sipuleucel-T. In an interim analysis reported during the 2013 Genitourinary Cancers Symposium in Orlando, Florida, concurrent administration of the immunostimulatory agents sipuleucel-T and abir­aterone acetate plus prednisone results in si­puleucel-T potency and prime boost similar to that of sipuleucel-T alone in men with mCRPC.13

Although some physicians prescribe secondary hormonal therapies after progression using ADT, such as ketoconazole, steroids, and estrogens, these drugs have significant side effects. Furthermore, none of these drugs have phase 3 clinical trial evidence demonstrating a significant improvement in OS. With the approval of 4 new therapeutic agents since 2010, many urologists now view the use of secondary hormonal maneuvers as a tactic that may adversely affect patient access to therapies with demonstrable survival benefits.

For men with prostate cancer to qualify for newer therapies, they must have documented mCRPC. However, the panelists consistently described challenges in the recognition and treatment of patients with mCRPC by urologists.

First, urologists must understand that patients with mCRPC do not always have symptoms or even a rising PSA.3 A recent study demonstrated that 32% of men who were thought to have nonmetastatic CRPC had evidence of metastases upon imaging.14

Second, urology practices must proactively identify patients with CRPC who might have metastatic disease and order appropriate imaging to evaluate them. Primary detection techniques include bone scan, 18F sodium fluoride (NaF) positron emission tomography (PET) scan, and computed tomography scan (for nodal metastases). The panelists indicated that NaF PET scanning is far more sensitive in detecting metastases than traditional bone scanning. Routine scanning of “at-risk” patients receiving ADT is not occurring for multiple reasons: the lack of national guidelines regarding the frequency and type of scans; concern that payers will not reimburse scan costs, particularly for NaF PET scans; and uncertainty regarding pa­tient selection and timing of scans. Of note, NaF PET scanning is reimbursed by Medicare, but only under the auspices of the National Oncologic PET Registry.15

Third, upon detection of metastatic disease, it is imperative for urologists and their patients to discuss treatment options, including sipuleucel-T and other appropriate agents. Treatment recommendations should always be made in accordance with product labeling.

The panelists outlined several steps that their and others’ urology practices have taken to address issues related to early detection of mCRPC. For example, the practices represented by the panelists typically designate 1 person—a nurse, patient navigator, or mid-level provider—to review patients’ charts and identify the signals of emerging metastatic disease. These professionals then notify urologists to order scans and evaluate treatment alternatives for identified patients.

Some urology practices have established their own protocols for routine bone scanning (eg, every 6-12 months for patients receiving ADT). Others are consulting proactively with local and regional payers to clarify payers’ positions regarding precertification and medical necessity requirements for PET scans and other diagnostic tests for suspected patients with mCRPC.

Progressive urology practices have developed bone health clinics for patients with prostate cancer who require Xgeva (denosumab) or Zo­meta (zolendronic acid). At Regional Urology (Shreveport, Louisiana) and The Urology Group (Cincinnati, Ohio), clinics have evolved into full-service CRPC clinics. Patients with CRPC are referred to these clinics within the practice after CRPC develops, with or without metastases. Urologists who have a special interest in prostate cancer management then direct the treatment of these patients.

In the discussion, participating urologists identified sipuleucel-T as a preferred treatment option for patients with newly diagnosed mCRPC. In addition to the clinical data supporting its use prior to chemotherapy (which urologists typically do not administer), panelists cited a number of advantages in treating appropriate patients with sipuleucel-T, including ease of administration and favorable safety profile. Treatment with sipuleucel-T also allows urologists to retain their patients longer, thereby extending the continuity of care in treating their disease.

About the Authors
Dr Raedler and Mr Welz are medical writers with Engage Healthcare Communications, and Dr Kirsh is President, The Urology Group, Cincinnati, Ohio

Author Disclosure Statement
Dr Raedler and Mr Welz have nothing to disclose. Dr Kirsch is a speaker and a consultant for Dendreon Corporation, and a speaker for Amgen and Bayer.


  1. US Cancer Statistics Working Group. United States Cancer Statistics: 1999–2009 Incidence and Mortality Web-based Report. Atlanta, GA: Centers for Disease Control and Prevention, and National Cancer Institute, US Department of Health and Human Services; 2012. Accessed September 2, 2013.
  2. Urology Care Foundation: Official Foundation of the American Urological Association. Prostate Cancer. Updated March 2013. Accessed August 14, 2013.
  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guideline®): Prostate Cancer. Version 4.2013. Accessed August 14, 2013.
  4. Abdulla A, Kapoor A. Emerging novel therapies in the treatment of castration-resistant prostate cancer. Can Urol Assoc J. 2011;5:120-133.
  5. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180-1192.
  6. Smith MR, Cook R, Lee KA, Nelson JB. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer. 2011;117:2077-2085.
  7. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30.
  8. Provenge [package insert]. Seattle, WA: Dendreon Corporation; 2011.
  9. Schellhammer PF, Chodak G, Whitmore JB, et al. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013;81:1297-1302.
  10. Zytiga [package insert]. Horsham, PA: Janssen Biotech, Inc; 2012.
  11. Xtandi [package insert]. San Francisco, CA: Astellas Pharma US, Inc; 2012.
  12. Xofigo [package insert]. Wayne NJ: Bayer HealthCare Pharmaceuticals, Inc; 2013.
  13. Small EJ, Lance R, Gardner TA, et al. A randomized phase II, open-label study of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) in metastatic castrate-resistant prostate cancer (mCRPC). Presented at: 2013 Genitourinary Cancers Symposium; February 14-16, 2013; Orlando, FL. Abstract 114.
  14. Yu EY, Miller K, Nelson J, et al. Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer. J Urol. 2012;188:103-109.
  15. National Oncologic PET Registry. What is the NOPR? Accessed September 4, 2013.

Panel Discussion

Richard G. Harris, MD
President and CEO
Melrose Park, Illinois
Jonathan Henderson, MD
Regional Urology, LLC
Shreveport, Louisiana
Gary M. Kirsh, MD
The Urology Group
Cincinnati, Ohio
Sharon Rouleau
Practice Manager
Urology Specialists, PC
Middlebury, Connecticut

Testing for Metastatic Castration-Resistant Prostate Cancer

A number of physicians on the panel highlighted the challenges that are associated with early testing to identify castration-resistant prostate cancer (CRPC) that has metastasized (mCRPC). The following exchange among several panelists illustrates some of the issues that affect urologists’ ability to proactively evaluate patients who are receiving androgen deprivation therapy (ADT).

Gary Kirsh (Moderator):  There is a tendency on the part of many urologists to think that if the patient is on Lupron and their prostate-specific antigen (PSA) level is rising slightly (ie, 2.0 ng/mL-4.0 ng/mL) that they are doing all right. But the fact is that many of them have metastases and we do not know that. We need to know that. Once we establish that they have mCRPC, we have a variety of therapeutic options that will actually extend their lives.

Richard Harris: It can be a hard message to get across. It is a long process to get some urology groups to realize that times have changed. They have to start looking at these patients. Now that we have good therapeutic options, we must not watch their PSA levels go up and do nothing.
One of the dilemmas is that there are no national testing guidelines right now. Everybody is going it alone. Urologists who specialize in prostate cancer have their own ideas about testing, but there are no guidelines. That is difficult for us.

Jonathan Henderson: We need to think about all of our patients with prostate cancer who are taking ADT, and who are becoming patients with CRPC. They metastasize before the PSA reflects that. In our practice, we routinely perform bone scans for patients who are receiving ADT to find the patients with CRPC before they are detected using PSA.

Dr Kirsh: The classic approach when you suspect metastatic disease is to order bone and computed tomography scans. Increasingly, we are using 18F sodium fluoride (NaF) positron emission tomography (PET) scanning, which is a better way of identifying bony metastases.

Sharon Rouleau: We had several patients with negative bone scans, but positive NaF PET scans. It started a controversy in our area. Radiologists went back to the bone scans and thought they had missed something; they could not understand how bone scans were negative and NaF PET scans were positive.

Dr Kirsh: The problem is that NaF PET is not covered by many commercial payers. It is covered by Medicare through a registry arrangement. We complete additional paperwork for each patient. I do not know why the test has not received widespread support from commercial payers, but clearly we need to go in that direction. It is probably more expensive than a technetium bone scan, but the results are significantly more reliable and accurate.

Dr Harris: We believe that the NaF PET scan is another tool that can be used to help confirm that the patient has metastases. Obviously, the presence of metastatic disease will affect the patient’s treatment plan.

Related Items
Ibrance (Palbociclib): First CDK4 and CDK6 Inhibitor FDA Approved for the Treatment of Postmenopausal Women with Metastatic Breast Cancer
Lisa A. Raedler, PhD, RPh
Oncology Practice Management - October 2015, Vol 5, No 7 published on October 13, 2015 in Drug Updates
Jakafi (Ruxolitinib): First FDA-Approved Medication for the Treatment of Patients with Polycythemia Vera
Lisa A. Raedler, PhD, RPh
Oncology Practice Management - June 2015, Vol 5, No 5 published on June 23, 2015 in Drug Updates
Akynzeo (Netupitant and Palonosetron), a Dual-Acting Oral Agent, Approved by the FDA for the Prevention of Chemotherapy-Induced Nausea and Vomiting
Lisa A. Raedler, PhD, RPh
Oncology Practice Management - May 2015, Vol 5, No 4 published on May 14, 2015 in Drug Updates
Nivolumab (Opdivo): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma
Lisa A. Raedler, PhD, RPh
Oncology Practice Management - February 2015, Vol 5, No 1 published on February 23, 2015 in Drug Updates
Zydelig (Idelalisib): First-in-Class PI3 Kinase Inhibitor Approved by the FDA for the Treatment of 3 Hematologic Malignancies
Lisa A. Raedler, PhD, RPh
Oncology Practice Management - December 2014, Vol 4, No 8 published on December 18, 2014 in Drug Updates
Beleodaq (Belinostat) Receives FDA Approval for the Treatment of Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma
Lisa A. Raedler, PhD, RPh
Oncology Practice Management - November 2014, Vol 4, No 7 published on November 11, 2014 in Drug Updates
Arzerra (Ofatumumab) Receives FDA Approval for Patients with Previously Untreated Chronic Lymphocytic Leukemia for Use in Combination with Chlorambucil
Lisa A. Raedler, PhD, RPh
Oncology Practice Management - October 2014, Vol 4, No 6 published on October 26, 2014 in Drug Updates
Peyronie’s Disease: An Underrecognized Men’s Health Condition
John A Welz, MPH
Stakeholder Perspectives in Men's Health August 2014 published on October 14, 2014
XIAFLEX (collagenase clostridium histolyticum): A New Option for the Treatment of Peyronie’s Disease
John A Welz, MPH
Stakeholder Perspectives in Men's Health August 2014 published on October 13, 2014
Zykadia (Ceritinib) Approved for the Treatment of Patients with Crizotinib-Resistant ALK-Positive Non–Small-Cell Lung Cancer
Lisa A. Raedler, PhD, RPh
Oncology Practice Management - August 2014, Vol 4, No 5 published on August 31, 2014 in Drug Updates
Last modified: October 17, 2013
  • American Health and Drug Benefits
  • Association for Value Based Cancer Care
  • Lynx CME
  • Oncology Practice Management
  • Rheumatology Practice Management