Worldwide, there are approximately 500,000 men diagnosed with prostate cancer each year, and in those men prostate cancer is the third most common type of malignancy, surpassed only by cancer of the lung and stomach.1 Other than nonmelanoma skin cancer, prostate cancer is the most commonly diagnosed male cancer in the United States.2 There is disparity in risk of prostate cancer diagnosis between races. Prostate cancer is more common in African American males than it is in white American males.3 Higher mortality is associated with late detection.4 The prevalence of prostate-specific antigen (PSA) screening has caused a drastic reduction in the number of patients who have distant metastatic disease at the time of diagnosis.5 For those patients who present with metastatic disease, local definitive therapy is no longer an appropriate option. The standard of care is systemic therapy.
Androgen deprivation therapy (ADT) remains the standard front-line treatment for metastatic prostate cancer. Patients can be treated with singleagent therapy gonadotropin-releasing hormone (GnRH) agonists, of which there are several options, or with combined androgen blockade, pairing GnRH with an antiandrogen such as bicalutamide. This therapy is widely effective; however, complications or side effects can include hot flushes, fractures, anemia, fatigue, loss of muscle mass and strength, and loss of libido, as well as changes in cognitive function. All of these side effects can potentially alter a patient’s quality of life (QOL), sometimes significantly. It is important for the practitioner to obtain a complete assessment of the side effects each patient is experiencing, as well as the consequences those effects have upon the patient’s QOL, and then to make clinical recommendations for palliative measures that can improve the patient’s QOL.
The majority of hormone-dependent cancers become castrate-resistant in about 1 to 3 years, resuming growth despite ADT.6 In 1996, the US Food and Drug Administration (FDA) approved mitoxantrone, at 12 mg/m2, in combination with corticosteroids, typically prednisone 5 mg twice daily, for the treatment of patients with pain related to advanced hormone-refractory prostate cancer, now known as castrate-resistant prostate cancer (CRPC). Prior to 2004, treatments for metastatic CRPC were palliative, without any proven survival benefit. Since that time, several therapies have emerged that have demonstrated a survival advantage.
Docetaxel in combination with prednisone was approved by the FDA in 2004 for the treatment of metastatic castrate-resistant disease. The 3-arm TAX 327 study, which led to FDA approval, compared docetaxel at 75 mg/m2 administered every 3 weeks, docetaxel at 30 mg/m2 weekly for every 5 of 6 weeks, and mitoxantrone at 12 mg/m2 every 3 weeks, each with prednisone 5 mg twice daily. The original analysis, done in August 2003, showed significantly better survival and response rates for pain, PSA, and QOL in the every-3-week docetaxel with prednisone group when compared with the mitoxantrone with prednisone group. Median survival time was 18.9 months (95% confidence interval [CI], 17.0-21.2) in the every-3-week docetaxel with prednisone arm, 17.4 months (95% CI, 15.7-19.0) in the weekly docetaxel and prednisone arm, and 16.5 months (95% CI, 14.4-18.6) in the mitoxantrone and prednisone arm.7 By March 2007, data on 310 additional deaths were obtained and updated. These data demonstrated a continued survival benefit for the every-3-week docetaxel with prednisone group. Median survival time was 19.2 months in the every-3-week docetaxel with prednisone arm, 17.8 months in the weekly docetaxel and prednisone arm, and 16.3 months in the mitoxantrone and prednisone arm (P = .004).8 The every-3-week docetaxel with twice-daily prednisone chemotherapy regimen has remained a standard of care for first-line therapy for metastatic CRPC since its FDA approval.
Cabazitaxel was approved by the FDA on June 17, 2010, in combination with prednisone for the treatment of patients with castrate-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen. This was the first therapy found to provide significant survival benefit in second-line metastatic castrate-resistant prostate cancer. A multinational phase 3 trial, known as TROPIC, included patients who were progressing either during or after docetaxel (cumulative dose ≥225 mg/m2). The patients were randomized to receive 10 mg per day of prednisone with an every-3-week infusion of either mitoxantrone at 12 mg/m2 or cabazitaxel at 25 mg/m2. Analysis revealed that the patients receiving cabazitaxel and prednisone demonstrated a statistically significantly longer overall survival compared with those receiving mitoxantrone and prednisone (P <.0001). The median survival in the cabazitaxel and prednisone group was 15.1 months compared with 12.7 months in the mitoxantrone and prednisone group. Progression-free survival was also found to be statistically significantly in favor of the cabazitaxel and prednisone arm. The most frequent grade 3/4 toxicity was neutropenia observed in 81.7% of patients treated with cabazitaxel and prednisone and 58.0% of those treated with mitoxantrone and prednisone. Rates of febrile neutropenia were 7.5% and 1.3%, respectively.9 In clinical practice, one may want to consider either growth-factor support or a dose reduction of the cabazitaxel, or sometimes both, in efforts to minimize the degree of neutropenia and its sequelae.
Sipuleucel-T, an autologous cellular immunotherapy, was approved by the FDA on April 29, 2010, to treat asymptomatic or minimally symptomatic metastatic CRPC. In a phase 3 study, patients were randomly assigned in a 2:1 ratio to receive either sipuleucel-T or placebo every 2 weeks, for a total of 3 infusions. Analysis showed that in the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (P = .03). This reduction represented a 4.1-month improvement in median survival. However, no significant effect on the time to objective disease progression was observed.10 The rationale for treating patients with sipuleucel-T can be a difficult concept for patients to understand, as it is typical for patients to have neither a drop in PSA nor any improvement in their imaging studies. Carefully detailed patient education is warranted to ensure that patients have an adequate understanding of the potential benefit they may receive from this therapy.
Abiraterone acetate, in combination with prednisone, is the most recently approved therapy for metastatic CRPC patients who have received prior docetaxel therapy, obtaining FDA approval on April 28, 2011. In the clinical trial that led to FDA approval, patients were randomized in a 2:1 ratio to receive abiraterone acetate, 1000 mg once daily in combination with prednisone 5 mg twice daily or placebo in combination with prednisone 5 mg twice daily. At the preplanned interim analysis, there was a 35% reduction in the risk of death. Overall survival was 14.8 months for the abiraterone acetate plus prednisone arm in comparison to 10.9 months in the placebo plus prednisone arm (P <.001).11 Abiraterone acetate has particular appeal to patients since it is administered orally. It should be taken on an empty stomach, and is generally well tolerated. Side effects that can be associated with elevated mineralocorticoid levels, due to CYP17 inhibition, include fluid retention/edema, hypokalemia, and hypertension. Liver function tests should be monitored routinely.
In addition to the aforementioned antitumor therapies, there are therapies available to decrease the risk of skeletal events, which are prevalent in this patient population. Zoledronic acid, an intravenous bisphosphonate, is used to reduce and delay bone complications due to bone metastases from solid tumors, including metastatic CRPC. As it is renally excreted, zoledronic acid requires dose adjustment in accordance with renal function. Patients with a normal creatinine clearance receive 4 mg intravenously over at least 15 minutes. Side effects can include flu-like symptoms, including arthralgias, myalgias, and fever.
Denosumab, a monoclonal antibody, was FDA approved on November 18, 2010, for the prevention of skeletal-related events in patients with bone metastases from solid tumors. A phase 3 trial was conducted, in which patients with metastatic CRPC were randomized 1:1 to receive either 120 mg subcutaneous denosumab plus intravenous placebo or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks. Median time to first on-study skeletal-related event was 20.7 months with denosumab compared with 17.1 months with zoledronic acid (P = .008).12 The most common adverse reactions for patients are fatigue/asthenia, hypophosphatemia, and nausea. In addition, severe hypocalcemia can occur. It is important that patients who receive this therapy take a daily calcium supplement.
Osteonecrosis of the jaw (ONJ), a rare complication, can occur with either zoledronic acid or denosumab. About 94% of published cases of ONJ are patients with multiple myeloma or metastatic carcinoma to the skeleton who are receiving IV nitrogen-containing bisphosphonates. The most important predisposing factors for the development of bisphosphonate-associated ONJ are the type and total dose of bisphosphonate and history of trauma, dental surgery, or dental infection.13 It is reasonable to require patients on these therapies to contact their treating practitioner’s office prior to dental appointments.
Caring for the patient with metastatic CRPC can be challenging; however, recent advancements in therapy have not only broadened the options for patients in this setting but have, more importantly, improved survival. Ongoing studies are investigating new treatments and include research in the areas of androgen manipulation, chemotherapy, and immunotherapy, to mention a few. Early results appear promising and potentially will not only expand the existing treatment arsenal but may also show survival benefit for patients who live with the devastating diagnosis of metastatic CRPC.
References
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