There is a dramatic revolution under way in the treatment of advanced-stage prostate cancer, which for many years consisted of systemic chemotherapy that offered only palliation of symptoms and no hope of improved survival. The last decade has witnessed the debut of a completely new arsenal of therapies that target prostate cancer— specific pathways that improve overall survival. These new medications include cabazitaxel (Jevtana), abiraterone acetate (Zytiga), enzalutamide (Xtandi), sipuleucel-T (Provenge), and radium-223. Denosumab (Xgeva or Prolia) represents another class of new drugs that can prevent bone-related complications. Prior to the advent of these new therapies, there was a well-defined therapeutic progression with available agents, but substantial changes are being felt by clinicians and their patients and new paradigms of sequencing are being developed. These advances aside, there are also considerations to be made for cost, not only those incurred by the patient, but by society as a whole.

Beyond survival improvements, research is also heavily focused on preventing skeletalrelated events (SREs) which broadly represent the costly (>$10,000 per event) and painful sequelae of skeletal metastases common to men with late-stage prostate cancer including pathologic fractures, bone deformation, need for radiation or surgery to bone, and spinal cord compression.

 While SREs represent a hard end point that can be quantified in trials, symptomatic benefit in the form of pain reduction and greater functional mobility may represent a better measure of overall efficacy of treatment as reported directly by patients. Therapies such as zoledronic acid (Zometa) and denosumab exploit very different biochemical pathways that focus on preventing SREs (and in the case of radium-223, also targeting prostate cancer for destruction). Despite the focus on SRE prevention with many of these therapies, not all studies have borne out improvements in pain, quality of life, or overall survival.

Now, practitioners must grapple with the increased complexity of options, indications, cost, patient selection, and side effects, and determine how best to select therapies for patients with varied health statuses and preferences. The 

 provides a quick look at these new agents, cost of treatment, and overall survival. This article will briefly examine newly approved treatments for castrationresistant prostate cancer (CRPC), their indications, toxicity profiles, and cost considerations, and evaluate their potential impact on quality of life, prevention of SREs, and overall survival.

		Table. Cost-Benefit Analysis and Indications for Various CRPC Treatments Now on the Market

					Overall survival improvement over placebo

		*Costs do not include physician fees and treatment of adverse events.

		CRPC indicates castration-resistant prostate cancer; mCRPC, metastatic castration-resistant prostate cancer.

		Source: Adapted with permission from Crawford ED, Flaig TW. Optimizing outcomes of advanced prostate cancer: drug sequencing and novel therapeutic approaches. Oncology (Williston Park, NY). 2012;26(1):70-77.

Docetaxel (Taxotere) was approved in 2004, displacing mitoxantrone as one of the few therapeutics available for the treatment of CRPC. CRPC is diagnosed when prostate-specific antigen (PSA) progression occurs with or without metastasis in spite of androgen-deprivation therapy (ADT) and resultant castrate levels of serum testosterone (<50 ng/dL). Docetaxel provided a 2.4-month increase in overall survival compared with mitoxantrone, while also providing improvements in reported pain levels. No differences in rates of progression or measurable disease were noted between the groups, however.

A second-line systemic chemotherapy, cabazitaxel, was approved in 2010 for men with metastatic CRPC who failed prior docetaxel use. When given every 3 weeks with prednisone, there was a significant improvement in overall survival of 2.4 months (15.1 vs 12.7 months) compared with mitoxantrone plus prednisone in men who were docetaxel resistant.

 Investigators noted a small improvement in progression-free survival (2.8 vs 1.4 months; 

 <.0001). Primary side effects included diarrhea, 7.5% rate of febrile neutropenia, and increased risk of death within 30 days of last dose of chemotherapy (5% in cabazitaxel vs 2% with mitoxantrone).

Abiraterone acetate was approved by the FDA in April 2011 for the treatment of men with docetaxel-resistant metastatic CRPC. This compound is orally available and irreversibly inhibits the CYP17A enzyme, a key step in steroid biosynthesis. Traditional ADT suppresses gonadal sources of testosterone, but this compound shuts down virtually all sources, including gonadal, adrenal, and intratumoral sources of testosterone production. Therapy in the phase III trial that led to its approval was well tolerated.

 Adverse events typically include edema (31%), hypokalemia (17%), and hypertension (10%). Median overall survival improved 3.9 months over placebo (14.8 vs 10.9 months; 

 <.001). Progression-free survival also favored abiraterone acetate (5.6 vs 3.6 months). A second phase III trial of abiraterone acetate in metastatic, chemotherapy-naÃ¯ve CRPC was recently completed and revealed a significant difference in progression-free survival along with a trend in survival improvement.

Enzalutamide (previously known as MDV3100, trade name Xtandi) was approved by the FDA in September 2012. It is a potent second-generation antiandrogen that has an affinity for the androgen receptor five times greater than the affinity of bicalutamide.

 Evaluated in the post-chemotherapy CRPC setting, it demonstrated a 4.8-month improvement in overall survival over placebo (18.4 vs 13.6 months).

 Importantly, quality of life was shown to be improved 43% versus 18%. Outcomes with respect to SRE, PSA, progression-free survival, and radiographic progression-free survival were all markedly better in the treatment arm. The most serious adverse event attributed to enzalutamide was seizures, which occurred in about 0.5% of patients.

Sipuleucel-T represents a first-in-class immunotherapy against prostate cancer. A patient’s antigen-presenting cells are collected via leukapheresis, sent for processing, and loaded with a fusion protein consisting of prostatic acid phosphatase (PAP) and granulocyte-macrophage colony— stimulating factor (GM-CSF). This is cultured and infused back into the patient, initiating a beneficial immune response. A phase III trial of 512 men with asymptomatic or minimally symptomatic metastatic CRPC found improved overall survival of 25.8 versus 21.7 months for placebo, notwithstanding 64% of men in the placebo arm having crossed over during the trial.

 Disease progression was not measurably different. Common reactions included chills, fever, and headache. The lack of PSA response as a marker of activity remains a challenge, particularly as sipuleucel-T is positioned at the forefront of current sequencing algorithms for CRPC (

) on the basis of clinical indications and the paucity of other low-toxicity therapies available to men in this disease category.

		Figure. Sequential Progression of Disease State and Corresponding FDA-Approved Therapies

		The bottom row includes potential drugs currently under study or proposed new indications for drugs approved under other disease states. Abiraterone acetate and enzalutamide are both currently under study in the chemotherapy-naÃ¯ve metastatic CRPC disease state. ADT indicates androgen-deprivation therapy; CRPC, castration-resistant prostate cancer; FDA, US Food and Drug Administration; LHRH, luteinizing hormone-releasing hormone; PCa, prostate cancer; PSA, prostate-specific antigen.

: Adapted with permission from Crawford ED, Flaig TW. Optimizing outcomes of advanced prostate cancer: drug sequencing and novel therapeutic approaches. Oncology (Williston Park, NY). 2012;26(1):70-77.

	Therapeutic Sequencing–Current Realities and Future Potential

Prior to the rapid introduction of the abovementioned agents, prostate cancer was generally treated systemically with hormone ablation in the form of GnRH agonists/antagonists. If disease progression occurred (confirmed with two consecutive PSA rises despite castrate levels of serum testosterone >50 ng/dL), CRPC is diagnosed.

 Patients could attempt secondary hormonal manipulation with the use of another GnRH agonist/ antagonist or non-specific inhibitors like ketoconazole that disrupt steroid biosynthesis. Beyond hormonal ablation, physicians turned to systemic chemotherapies such as docetaxel for patients with aggressive symptomatic disease. Other interventions, like radiotherapy to bone metastasis, serve a palliative role and can offer relief in a cost-effective manner.

Now, however, there are at least five new therapies that improve overall survival, each with specific indications for utilization in addition to the adjunctive therapies that mitigate SREs from metastases. The Figure outlines current disease states under which these new agents are currently approved for use. Also shown are new therapeutics in phase III trials, and possible new scenarios for currently available therapies, some of which are under study, such as abiraterone in patients with chemotherapy-naÃ¯ve metastatic CRPC.

Unfortunately, no randomized controlled trials directly compare the activity of these new agents, so practitioners must instead rely on side-effect profiles to guide patient selection. A rational approach to therapy selection is certainly called for and should take into account overall cost and significant improvements in quality of life (as measured by reduction in SREs, pain scores, and functional mobility). Future trials are needed to address several important questions: whether earlier initiation of agents in the disease course affects outcomes, how combination or adjuvant therapies perform (are they additive, synergistic, or neither), can varied sequencing improve time to disease progression and overall survival, and what therapies offer the best cost-to-benefit ratio with regard to maintaining quality of life? Prostate cancer remains a very heterogeneous disease, even in advanced stages, and clinical trials initiated in earlier disease states take longer to assess such outcomes. In the past, PSA was considered a surrogate marker of disease outcomes; however, the FDA does not consider PSA-related markers of progression as evidence for activity, as the correlation with overall survival is quite variable.

Despite the huge advances made in the development of these targeted therapies, cost-effective oncologic care will most likely occur when physicians successfully prevent progression and they minimize side-effect profiles of treatment.

The dramatic changes afoot in prostate oncologic care have created new opportunities to lengthen overall survival, increase quality of life, and reduce disease burden, and to alter the incidence of SREs. Physicians will need to consider each patient’s performance status and disease state in order to effectively choose beneficial treatments. Future studies will need to examine these agents head-to-head in order to best determine sequencing, and examine their use, particularly those with small sideeffect profiles in earlier disease states, and determine their effect on overall survival. Combinations of these agents should be studied. The elusive cures for many cancers will be formulated by attacking concurrent pathways using multiple agents.

 Dr Crawford has received consultancies from Poinard, Indevus, honoraria from UBM Medica, and lecture fees from sanofi-aventis, Poinard, AstraZeneca, GlaxoSmithKline, and Ferring. Dr Rove has received honoraria from Turner White Communications and UBM Medica.

 E. David Crawford, MD, Division of Urology, University of Colorado, Anschutz Medical Campus, PO Box 6510, Mailstop F743, Aurora, CO 80045. E-mail: 

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Articles

There is a dramatic revolution under way in the treatment of advanced-stage prostate cancer, which for many years consisted of systemic chemotherapy that offered only palliation of symptoms and no hope of improved survival.

E. David Crawford, MD, & Kyle O. Rove, MD

Articles

Advanced Prostate Cancer: Therapeutic Sequencing, Outcomes, and Cost Implications