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Challenges in Treating Advanced Disease

Published Online: December 30, 2013
Daniel P. Petrylak, MD
Castration-resistant prostate cancer (CRPC) has historically presented significant challenges to both clinicians and patients in regard to disease progression and consequent management. The first advances in the treatment of this state of prostate cancer with docetaxel chemotherapy demonstrated a survival benefit over the palliative standard of care, mitoxantrone combined with prednisone. The recognition that these patients still maintained active androgen receptor access identified new therapeutic agents for CRPC that aimed to further deplete testosterone levels or directly interact with the androgen receptor (ie, enzalutamide). Other therapeutic targets that have established efficacy in randomized phase 3 trials include bone metastases (ie, radium 223 dichloride), the immune system (ie, sipuleucel-T), and tubulin (ie, cabazitaxel). These new and evolving agents are positioned to substantially alter the therapeutic environment for CRPC and to improve patient outcomes and quality of life.

(Am J Manag Care. 2013;19:S366-S375)
Management of Castration-Resistant Prostate Cancer: Where Have We Been and Where Are We Going?

While patients with localized prostate cancer (PrCa) may have the disease eradicated with local treatments such as radical prostatectomy or radiation therapy (RT), the treatment of advanced disease involves systemic therapy such as androgen blockade, chemotherapy, and isotope therapy. Androgen deprivation therapy (ADT) with a luteinizing-hormone-releasing hormone (LHRH) agonist or antagonist is typically administered as first-line therapy.1 Unfortunately, progression of disease after initial response to androgen blockade (termed castration-resistant prostate cancer or CRPC) is heterogeneous, and is marked by any or all of the following criteria: (1) rising PSA; (2) progression of bone metastases; or (3) progression of visceral or soft tissue lesions. This disease progression occurs despite castrate levels of testosterone (<50 ng/mL).1-4 Patients may also present for the first time with castration-resistant disease, although fewer than 5% of men diagnosed with PrCa initially present with evidence of metastases.1

The prognosis for patients with CRPC is heterogeneous and is related to numerous clinical factors, such as pain, weight loss, performance status, and markers related to the extent of disease, such as hemoglobin, lactate dehydrogenase (LDH), alkaline phosphatase, and the sites of disease.5  However, investigational trials over the past 20 years have revolutionized therapy for CRPC. Research has led to the discovery and further advancements of a select group of chemotherapies, hormonal treatments, immunotherapies, and palliative agents that have been approved by the US Food and Drug Administration (FDA) for use in patients with CRPC, and some therapies have been shown to improve survival. Other therapies are still undergoing investigation in preclinical and clinical trials to continue the discovery of optimal treatment regimens that will delay disease progression, maximize patient survival time, and minimize side effects to improve clinical outcomes and quality of life (QOL) in patients with advanced, castration-resistant disease.1

In May 2013, the American Urological Association (AUA) published an updated classification system that identified 6 types of “index patients” with CRPC to serve as a basis for treatment decisions. These 6 index patients were believed to represent the most common clinical scenarios encountered in practice for managing patients with CRPC. These patient models were created with variations that depend upon the presence or absence of metastases, degree of symptoms, performance status, and prior treatment with “standard of care” docetaxel-based chemotherapy or lack thereof7:

  1. Asymptomatic non-metastatic CRPC
  2. Asymptomatic or minimally symptomatic metastatic CRPC (mCRPC) with no prior docetaxel therapy
  3. Symptomatic mCRPC with good performance status and no prior docetaxel therapy
  4. Symptomatic mCRPC with poor performance status and no prior docetaxel therapy
  5. Symptomatic mCRPC with good performance status and prior docetaxel therapy
  6. Symptomatic mCRPC with poor performance status and prior docetaxel therapy
The overriding goal of this guideline update was to provide classifications for evidence-based recommendations for the treatment of patients with CRPC, allowing for better individualization of management strategies for castration-resistant disease.7 However, CRPC is a biologically heterogeneous disease, and evidence is not yet sufficient to formulate appropriate guidance for therapy based on individual tumor biology.

Systemic Chemotherapy in CRPC: Evolving Standards of Care

Numerous phase 2 clinical trials have evaluated single- agent chemotherapy for CRPC, including agents from drug classes such as the anthracyclines, alkylating agents, antimetabolites, platinum-based agents, and topoisomerase inhibitors.8-10 An analysis of 26 trials that assessed various chemotherapies (prior to the advent of routine PSA assessment used to gauge treatment effectiveness) found that the response rate, defined as patients who achieved complete or partial response according to National Prostate Cancer Project criteria, exceeded 10% in 6 of the 26 trials and averaged 8.7% (95% confidence interval [CI], 6.4%-9.0%) in patients with CRPC treated with single-agent therapy.10 The combination of mitoxantrone plus prednisone was the only chemotherapeutic option for patients with CRPC, and has been found to provide palliative benefits with reductions in pain and improved QOL.1,11 This practice pattern shifted when docetaxel plus prednisone or docetaxel plus estramustine became the leading combinations as the evidence-based standard in chemotherapy, and the first-line treatment for castration-resistant disease. Another novel agent, cabazitaxel, has been studied and approved for second-line chemotherapy after failure of docetaxel-based chemotherapy in patients with mCRPC.1,8

Docetaxel

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