In men, prostate cancer is the most commonly diagnosed solid tumor malignancy in the United States and is the second highest cancer-specific cause of death after lung cancer.1
At time of diagnosis, most individuals with prostate cancer are asymptomatic. Screening and identification of prostate cancer is normally based on prostate-specific antigen (PSA) testing and a digital rectal examination, and the diagnosis is typically confirmed by a needle biopsy. If the biopsy results are positive, the affected tissue is graded based on microscopic evaluation and a Gleason score is calculated. The Gleason score is used to predict prognosis and help guide initial therapy.2
Although Gleason grading and scoring has been the gold standard of risk classification in prostate cancer for many years, there are emerging techniques that may be incorporated into the physician’s armamentarium in the future.
Today’s screening and identification techniques find most patients with prostate cancer, and only approximately 5% of newly diagnosed prostate cancer patients in the United States present with metastatic disease.3
With the change in the US Preventive Services Task Force guidance regarding routine PSA screening in men age 50 years and older, some urologists are concerned that the percentage of newly diagnosed patients with metastatic disease may begin to increase, reversing a trend whereby the incidence of newly diagnosed patients with metastatic prostate cancer had dropped from 67 per 100,000 in 1990 to 23 per 100,000 in 2005—a 66% decrease.4,5
Herein lies the conundrum. On the one hand, some stakeholders have with advanced prostate cancer. There are a number of different agents characterized as ADT. The most recognizable brand marketed in the United States is Lupron (leuprolide acetate). In addition to ADT, urologists may or may not add a secondary antiandrogen agent such as nilutamide, bicalutamide, or flutamide.7
It is important to recognize that ADT can have a number of side effects, including hot flashes and flushing; bone demineralization, which can lead to osteoporosis; and central weight gain and insulin resistance, which may contribute to the onset of diabetes and cardiovascular disease. In recent years, urologists have gained a better understanding of those toxicities. Even though ADT is often started early, patients are receiving better nutritional and cardiovascular care than in the past.
Nonetheless, overuse of ADT remains a concern. It is recommended for adjuvant therapy with radiation in intermediate-, high-, and very high-risk patients, and in patients with metastatic disease.7
A number of antiandrogen therapies, including leuprolide, goserelin, triptorelin, and histrelin, are available in the United States for palliative treatment of advanced prostate cancer. Antiandrogens are frequently prescribed to patients with prostate cancer after PSA relapse, although not specifically indicated for this population. In addition, starting ADT in patients with asymptomatic metastatic disease remains controversial.8-12
In castration-recurrent prostate cancer (CRPC), the patient progresses despite primary androgen deprivation therapy or bilateral orchiectomy. CRPC is characterized by a rising PSA level despite a testosterone level <50 ng/dL.7,13 There are a number of treatment options for CRPC, as noted in guidance from NCCN.7
Cytotoxic chemotherapeutic agents for the treatment of patients with advanced prostate cancer include docetaxel and cabazitaxel. In 2004, Taxotere (docetaxel) was approved for use in patients with metastatic CRPC. Taxotere is administered concomitantly with prednisone. Although 20% to 30% of patients have grade 3 and grade 4 toxicities, the majority of patients tolerate Taxotere reasonably well. Given in combination with prednisone every 3 weeks, Taxotere gives patients a 2.4-month overall survival advantage compared with mitoxantrone and prednisone.14
Jevtana (cabazitaxel), a microtubule inhibitor indicated in combination with prednisone, was approved in 2010 for patients previously treated with a docetaxel-containing treatment regimen. Jevtana has demonstrated a 2.4-month overall survival advantage compared with mitoxantrone and prednisone in this patient population.15
Until recently, most patients who progressed despite ADT were given cytotoxic chemotherapy. However, the treatment landscape has been changing, and there have been several new developments in treating patients with metastatic CRPC (Table).
Provenge (sipuleucel-T), which was approved in 2010, is an immunotherapeutic agent with a 4-week to 6-week course of therapy that is indicated for asymptomatic or minimally symptomatic disease. In 2 clinical studies, patients taking Provenge had a 4.1-month and a 4.5-month overall survival advantage compared with controls. In clinical trials, the most common adverse events reported in patients treated with Provenge were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Serious adverse events included acute infusion reactions, cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.16
Zytiga (abiraterone acetate), an oral agent given once daily in conjunction with prednisone, was initially approved in 2011 for patients with metastatic CRPC after cytotoxic chemotherapy, and in December 2012, received US Food and Drug Administration approval for patients with metastatic CRPC prior to cytotoxic chemotherapy. In a clinical trial, patients achieved a 35.3-month median overall survival with Zytiga and a near doubling of radiographic progression-free survival. In addition, for patients taking Zytiga, median time to initiation of cytotoxic chemotherapy was 25.2 months. The side effects of Zytiga may 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 Zytiga. In the postchemotherapy setting, the phase 3 Zytiga trial improved survival by a median time of 3.9 months in the primary survival analysis and 4.6 months in an updated survival analysis.17
Another oral agent, Xtandi (enzalutamide), was approved as monotherapy in September of 2012 for patients with metastatic CRPC who have previously received docetaxel. Xtandi is given once daily, and was shown to extend overall survival by 4.8 months. Side effects that require monitoring include fatigue, diarrhea, hot flushes, and headache. In a pivotal phase 3 clinical trial, 7 patients receiving Xtandi reported seizures versus no patients in the placebo group. Overall, however, Xtandi is regarded as a well-tolerated drug.18
Although some physicians prescribe secondary therapies after progression on ADT, such as ketoconazole, steroids, and estrogens, these drugs all have significant side effects and none have been shown in a phase 3 trial to improve overall survival. With new therapeutic agents available, some urologists are beginning to view secondary hormonal maneuvers as a delaying tactic that may adversely affect patient access to approved therapies with demonstrable survival benefit.
The approval of 3 new (not cytotoxic) agents since 2010 is changing the way that urologists may think about advanced prostate cancer. Although some urologists are beginning to incorporate these therapies into clinical practice, panelists noted 2 primary barriers to entry. First, physicians are often slow to change their practice patterns. After a period of cumulative clinical experience, they can develop a comfort level prescribing newer therapies, even for agents with new side effects, as long as toxicities are manageable and outcomes are relatively predictable. Conversely, urologists may initially have concerns about managing toxicities for unfamiliar drugs. In addition to clinical considerations, it may be necessary to dedicate staff and resources to develop the clinical and business infrastructure to support adoption of new agents. Furthermore, practices may also need to develop expanded data collection and reporting mechanisms to provide payers with information to support quality initiatives or risk management programs.
Although it may require an initial investment, many practices find that adoption of newer agents, including oral therapies, allows them to better serve their patients with CRPC. The urologists represented on the panel agreed that these agents are efficacious and have manageable toxicities and improved outcomes. Furthermore, there was general agreement from the panel that new oral therapies allow the clinical practice to retain patients and provide continuity of care.
Author Disclosure Statement
Mr Welz has nothing to disclose. Dr Shore is a consultant to Amgen, Astellas, Bayer, Dendreon, Ferring, Janssen, Millennium, and Medivation.
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.
2. Urology Care Foundation: Official Foundation of the American Urological Association. Prostate Cancer. http:// www.urologyhealth.org/urology/index.cfm?article=146. Updated March 2013. Accessed April 22, 2013.
3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30.
4. American Urological Association. Information Sheet: Prostate-Specific Antigen (PSA) Testing for the Early Detection of Prostate Cancer. 2012.
5. Etzioni R, Gulati R, Tsodikov A, et al. The prostate cancer conundrum revisited: treatment changes and prostate cancer mortality declines. Cancer. 2012;118: 5955-5963.
6. American Cancer Society. Prostate Cancer Overview. http://www.cancer.org/cancer/prostatecancer/detailed guide/prostate-cancer-survival-rates. Updated January 17, 2013. Accessed April 22, 2013.
7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 2.2013. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed April 11, 2013.
8. Lupron Depot [package insert]. North Chicago, IL: AbbVie Inc; 2013.
9. Eligard [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; 2013.
10. Zoladex [package insert]. Wilmington, DE: Astra Zeneca Pharmaceuticals LP; 2012.