Pharmacologic treatment of prostate cancer

Prostate cancer is the most frequently diagnosed cancer, aside from non-melanoma skin cancer, in men in the United States.¹ According to the American Cancer Society, an estimated 233,000 new cases of prostate cancer and an estimated 29,480 deaths from prostate cancer will have occurred in the United States during 2014.¹ About 60% of all prostate cancer cases are diagnosed in men aged 65 years and older, and 97% of cases occur in men aged 50 and older.¹ The incidence of prostate cancer is 60% higher in African Americans than in whites.¹

Treatment of prostate cancer depends on the stage of disease. For patients with early stage, low-risk, organ-confined disease, surgery, radiation therapy, and androgen deprivation therapy (ADT) are the standard treatments. For patients with advanced or metastatic prostate cancer, ADT, cytotoxic chemotherapy, radiopharmaceuticals, or immunotherapy is used.^2-5 This article reviews current pharmacologic therapies and newly approved agents for advanced or metastatic prostate cancer. The use of radiopharmaceuticals for the treatment of prostate cancer is beyond the scope of this article.

Pharmacologic agents for advanced or metastatic disease

Androgens, such as testosterone, play an important role in regulating the growth and maintenance of the normal prostate epithelium and are considered to be initiators for promoting the growth of prostate cancer.⁶ When deprived of androgen stimulation, the prostate gland rapidly involutes and the glandular cells undergo apoptosis. In 1941, Huggins and Hodges reported that surgical castration with orchiectomy or medical castration with estrogen therapy in patients with metastatic prostate cancer resulted in amelioration of symptoms in a large number of patients.³ Today, more than 70 years later, the initial treatment for metastatic prostate cancer still includes suppressing testicular androgen production by medical or surgical castration.

Despite achieving castrate levels of testosterone through medical or surgical castration, many patients with prostate cancer will experience disease progression, evidenced by rising levels of prostate-specific antigen (PSA) or metastatic disease. Formerly, these patients were referred to as having hormone-refractory prostate cancer. More recently, however, it has become understood that these prostate cancer cases are not refractory to hormonal therapies, but are actually sensitive to even very low levels of androgen for promotion of growth. These cases are therefore more accurately referred to as castration-resistant (or castration recurrent) prostate cancer (CRPC).⁷ The optimal treatment of patients with CRPC without evidence of metastases is unclear. For patients who develop metastatic CRPC (mCPRC), secondary hormone therapies, cytotoxic chemotherapy, radiopharmaceuticals, or immunologic therapies can be used.

Androgen deprivation therapy

ADT, also known as androgen suppression therapy, is based on the reduction of androgen hormones by orchiectomy (surgical castration) or medications (medical castration). Commonly used ADT medications include antiandrogens, androgen biosynthesis inhibitors, and gonadotropin-releasing hormone (GnRH) receptor agonists and antagonists (Table 1, Figure 1).

NEXT: The difference between gonadotropin-releasing hormone agonists and gonadotropin-releasing hormone antagonists.

Gonadotropin-releasing hormone agonists

GnRH is released from the hypothalamus and stimulates release of luteinizing hormone (LH) from the pituitary. LH can stimulate Leydig cells in the testes to synthesize and release testosterone. GnRH agonists, also known as GnRH analogues, include goserelin, histrelin, leuprolide, and triptorelin. GnRH agonists are a recommended option in the National Comprehensive Cancer Network (NCCN) guidelines as first-line therapy for the treatment of advanced or metastatic prostate cancer.⁴ No preference is given to the use of one agent over another. All GnRH agonists will cause an initial surge in testosterone production, followed by a decline in testosterone production to castrate levels, which is caused by a negative feedback mechanism, approximately 2 to 4 weeks after administration. Side effects common to all of the GnRH agonists include “tumor flare,” or an initial worsening of prostate cancer-related symptoms, such as urinary retention, pain, and spinal cord compression, due to the initial increase in testosterone production.⁸ Symptoms of tumor flare can be lessened with the addition of antiandrogens, such as bicalutamide, for at least 7 days after initiation of GnRH agonist therapy.⁴ Other common side effects of GnRH agonists are related to castrate levels of testosterone and include sexual dysfunction, osteoporosis, hot flashes, fatigue, anemia, and metabolic changes.^9–12 Most GnRH agonists are administered as subcutaneous or intramuscular injections every 1 to 6 months, depending on the formulation (Table 2).⁸ Histrelin is administered just once every 12 months, but requires surgical placement of the subcutaneous implant.

Gonadotropin releasing-hormone antagonist

Degarelix is an antagonist of GnRH that reversibly binds to GnRH receptors in the anterior pituitary gland, blocks the receptor, and decreases the secretion of LH and follicle-stimulating hormone, which results in rapid androgen deprivation by decreasing testosterone production. Degarelix has been approved by FDA for the treatment of men with hormone-sensitive advanced prostate cancer. In contrast to the GnRH agonists, degarelix has an immediate onset of action and does not cause the initial surge in testosterone levels that can lead to symptoms of tumor flare in advanced prostate cancer patients.^13,14

Phase 3 data for degarelix 240 mg subcutaneously followed by 160 mg or 80 mg monthly versus leuprolide 7.5 mg intramuscularly monthly showed that, in the first treatment year, degarelix was as effective at suppressing testosterone to castrate levels and was associated with a lower risk of PSA failure or death compared to leuprolide.^15,16 Injection-site reactions were more common in the degarelix group.¹⁵ At present, the advantage of degarelix over GnRH agonists is the lack of inducing symptoms of tumor flare, which often needs to be prevented by the addition to antiandrogens to GnRH agonist therapy, during the first weeks of therapy. However, degarelix must be dosed monthly and may offer a less convenient dosing schedule than GnRH agonists, which are available in every 3 to 12 month formulation. In addition, a 30-day supply of degarelix may be more costly than treatment with a GnRH agonist, like leuprolide.

NEXT: First-generation and second-generation antiandrogens

Antiandrogens

Antiandrogens are nonsteroidal inhibitors of the androgen receptor that prevent the binding of dihydrotestosterone and testosterone and thereby prevent testosterone stimulation of growth of prostate cancer cells. Side effects common to all of the antiandrogens include sexual dysfunction, gynecomastia, diarrhea, and hepatic toxicity.⁸

First-generation antiandrogens. First-generation antiandrogens include bicalutamide, nilutamide, and flutamide. In patients with advanced or metastatic prostate cancer, antiandrogen monotherapy appears to be less effective than medical or surgical castration and thus is not indicated as first-line therapy.⁴ Antiandrogens have also been used in combination with other treatments for maximal androgen blockade (MAB).^17,18 A small survival benefit was found from MAB with flutamide and nilutamide, but more toxicity and concomitant decline in quality of life (QOL) were also observed.^17,18 As previously mentioned, combined androgen blockade (CAB) with an antiandrogen plus GnRH agonist can be used to prevent symptoms of tumor flare when first initiating therapy with a GnRH agonist. Continued CAB, however, has not been shown to result in improved survival outcomes compared to therapy with a GnRH agonist alone and therefore cannot be recommended.⁴ Antiandrogens may also be used as secondary hormone manipulation in patients with CRPC.⁴ Although the mechanism is not understood, withdrawal of antiandrogen therapy can cause a decrease in PSA and may be another therapeutic option in patients with CRPC.⁴ Side effects associated with specific first-generation antiandrogens include fatal hepatic toxicity with flutamide, and night blindness, alcohol intolerance, and pulmonary toxicity with nilutamide.⁸ Due to its more favorable side-effect profile, bicalutamide may be preferred over the other first-generation antiandrogens, flutamide and nilutamide. Unlike GnRH agonists and antagonists, antiandrogens are administered orally on a daily basis.

Second-generation antiandrogens. Treatment with first-generation antiandrogens has been found to be associated with increased expression of the androgen receptor (AR), which may lead to resistance to antiandrogen therapy. The second-generation antiandrogen, enzalutamide, has the ability to retain antagonism of testosterone in cells overexpressing AR.¹⁹ Enzalutamide is a pure androgen receptor signaling inhibitor with 5-fold higher binding affinity for the AR compared to bicalutamide. Unlike bicalutamide, it also prevents nuclear translocation and DNA binding of the AR and induces apoptosis without agonist activity.¹⁹

Enzalutamide was approved by FDA in August 2012 for the treatment of men with mCRPC with or without visceral metastases who have previously received docetaxel. In the pivotal phase 3 trial, patients were randomized to receive either enzalutamide 160 mg orally once daily or placebo. Overall survival was 18.4 months in the enzalutamide group compared to 13.6 months in the placebo group (P<0.001).²⁰ Common adverse effects observed in the enzalutamide group included fatigue, diarrhea, and hot flashes. Seizures have also been observed in patients receiving enzalutamide in both phase 1/2 and phase 3 trials.^20,21 Analysis of a phase 3 study comparing enzalutamide to placebo in asymptomatic or minimally symptomatic chemotherapy-naïve men with mCRPC with or without visceral metastases, showed a 29% reduction in risk of death in patients receiving enzalutamide.²² These results led to a 2014 revision in the original FDA indication to include all men with mCRPC.

NEXT: Androgen biosynthesis inhibitors and cryotoxic chemotherapy agents

Androgen biosynthesis inhibitor

Medical or surgical castration leads to reduction of testosterone and dihydrotestosterone by the testes, but the adrenal glands and even prostate cancer cells themselves continue to produce small, but significant, amounts of androgens. In CRPC, therefore, inhibition of extragonadal production of androgens may be beneficial.

Abiraterone acetate. In December 2012, the FDA announced approval of abiraterone in combination with low-dose prednisone for use in men with mCRPC prior to receiving chemotherapy. The drug was initially approved in 2011 for use in men with mCRPC that had progressed after treatment with docetaxel.

Unlike other ADT drugs, abiraterone does not affect the secretion of testosterone but inhibits its synthesis in the body. Abiraterone selectively and irreversibly inhibits the CYP17 (17 alpha-hydroxylase and C17,20-lyase) enzyme, which is expressed in testicular, adrenal, and prostatic tissues and is responsible for the biosynthesis of testosterone, dehydroepiandrosterone, and androstenedione.²³

In a phase 3 trial, men with mCRPC with or without visceral metastases who had previously received docetaxel were randomized to receive prednisone 5 mg orally twice daily with either abiraterone 1,000 mg orally daily or placebo.²⁴ Overall survival in the abiraterone group was 15.8 months, versus 11.2 months in the placebo group (P<0.0001).²⁴ In a similar study in asymptomatic or minimally symptomatic patients without prior exposure to chemotherapy and without visceral metastases, radiographic progression-free survival was 16.5 months in the abiraterone group and 8.3 months in the placebo group (P<0.001), with a trend towards improved overall survival.²⁵

Abiraterone is available in 250-mg capsules and is administered as 1,000 mg orally once daily. Due to its mechanism of action, treatment with abiraterone will result in excess production of aldosterone. Therefore, reversible and manageable adverse effects due to mineralocorticoid excess, such as hypertension, edema, and hypokalemia, are to be expected with abiraterone.⁸ Administration of low-dose prednisone concurrently with abiraterone is required to induce adrenal suppression and reduce excess production of aldosterone.⁸

Cytotoxic chemotherapy agents

Taxanes, such as docetaxel and cabazitaxel, are microtubule inhibitors that promote the assembly of microtubules from tubulin dimers and inhibit the depolymerization of tubulin, which results in stabilization of microtubules in the cell. This causes inhibition of cell division, cell cycle arrest and inhibition of tumor proliferation. Taxanes used alone or in combination with other agents have demonstrated efficacy in the treatment of mCRPC.

Docetaxel is FDA-approved as first-line chemotherapy in patients with mCRPC.

The results of a 2006 meta-analysis of 47 randomized trials of estramustine, 5-fluorouracil, cyclophosphamide, doxorubicin, mitoxantrone, and docetaxel in patients with mCRPC showed that only docetaxel showed a significant improvement in overall survival compared to best standard of care.²⁶ Docetaxel every 3 weeks plus continuous prednisone improved survival by 2.4 months (18.9 vs. 16.5 months) in comparison to mitoxantrone plus prednisone, which was previously approved as standard therapy for mCRPC.²⁷ Docetaxel has also been combined with various agents, such as bevacizumab, calcitriol, and estramustine, in an effort to further improve outcomes, although overall survival has not been extended compared to docetaxel plus prednisone.²⁸

For patients with mCRPC, an intravenous infusion of docetaxel at a dose of 75 mg/m² every 3 weeks (in combination with prednisone) is recommended. Common side effects observed with this dosing regimen include sensory neuropathy, diarrhea, fatigue, fluid retention, neutropenia, taste alterations, stomatitis, alopecia, and nail changes.^8,28

Unfortunately, a significant proportion of men will not respond to docetaxel-based therapy, and many patients will ultimately develop resistance to the therapy. Repeated treatment with docetaxel, similar to treatment with many other cytotoxic chemotherapeutic agents, will cause the tumor cells to develop resistance to the agent via multiple mechanisms, such as mutation of drug targets, or up-regulation of detoxifying enzymes or transporters that cause efflux of drugs out of the cell.²⁹

NEXT: Cabazitaxel and mitoxantrone

Cabazitaxel is FDA-approved as second-line chemotherapy in patients with mCRPC who have previously received treatment with docetaxel.

Prior to 2010, docetaxel was the only chemotherapy agent that had been shown to improve overall survival, symptom control, and QOL in patients with mCRPC. However, many patients may stop responding to docetaxel due to development of drug resistance. Overexpression of the multidrug resistance (MDR) transporter gene has been found to be the dominant mechanism for the development of resistance to docetaxel. Although cabazitaxel shows comparable cytotoxicity in prostate cancer cells sensitive to docetaxel, it has a much lower affinity for the MDR transporters than docetaxel and is thus more potent than docetaxel in cancer cells with acquired resistance to docetaxel.^30-33

The activity of cabazitaxel in patients with docetaxel-resistant prostate cancer was confirmed in an open-label phase 3 trial in 755 men with mCRPC progressing after treatment with docetaxel.³⁴ Patients were randomized to receive either cabazitaxel or mitoxantrone, both given intravenously every 3 weeks in combination with prednisone. The median survival in the cabazitaxel and mitoxantrone groups were 15.1 and 12.7 months respectively, with a hazard ratio for death of 0.70 (95% CI, 0.59–0.83; P<0.0001). Cabazitaxel was the first treatment shown to prolong survival of patients with mCRPC in the post-docetaxel setting.

Cabazitaxel is given as an intravenous infusion at a dose of 25 mg/m² once every 3 weeks (in combination with prednisone). Premedication with a combination of corticosteroid, H₁-and H₂-histamine receptor antagonists is recommended to prevent allergic reactions. Treatment with cabazitaxel requires careful monitoring and management of emerging symptoms due to the high incidence of neutropenia, febrile neutropenia, and diarrhea.³²

Mitoxantrone can intercalate into DNA and cause cross-links and strand breaks, and can bind to nucleic acids and inhibit DNA and RNA synthesis by template disordering and steric obstruction. It was approved by the FDA in 1996 for use in patients with mCRPC based on an improvement in pain and QOL outcomes, without an improvement in survival.³⁵ Since that time, however, docetaxel and cabazitaxel have been shown to be superior to mitoxantrone in prolonging survival of patients with mCRPC in either the first- or second-line chemotherapy settings.^27,34 According to guidelines from the NCCN, mitoxantrone plus prednisone may be considered for palliation of symptoms in patients with symptomatic mCRPC who are not candidates for taxane-based therapy.⁴

For patients with mCRPC, the approved dose of mitoxantrone is 12 to 14 mg/m² given as an intravenous infusion every 3 weeks, usually in combination with corticosteroids. Common side effects observed with mitoxantrone include neutropenia, nausea, fatigue, anorexia, and alopecia. Potentially serious adverse effects, such as decreases in left ventricular ejection fraction and secondary acute myeloid leukemias, have been reported.⁸

Other drugs. Other chemotherapeutic agents that may be used in prostate cancer patients include the topoisomerase II inhibitors etoposide and doxorubicin, the alkylating agent cisplatin, and the pyrimidine analog 5-fluorouracil.⁸

NEXT: Immunologic agents and conclusion

Immunologic agents

Sipuleucel-T is the first autologous cellular immunotherapy approved by FDA for patients with asymptomatic or minimally symptomatic mCRPC .

Sipuleucel-T can stimulate an immune response against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancer tissues. Production of sipuleucel-T is a complex process. Peripheral blood is first collected from the patient via leukapheresis, from which antigen-presenting cell (APC) precursors, consisting of CD54-positive cells that include dendritic cells, are isolated. The APCs are then sent to a specific central processing facility and activated in vitro with a recombinant human fusion protein, PAP-GM-CSF (also termed PA2024), composed of PAP linked to granulocyte-macrophage colony-stimulating factor (GM-CSF). The final product of sipuleucel-T is then shipped back to the patient’s location and reinfused into the patient, inducing T-cell immunity to tumors that express PAP.³⁶

Men with nonvisceral mCRPC and good performance status were randomized to receive sipuleucel-T or placebo infused every 2 weeks for a total of 3 doses in a double-blind, phase 3 clinical trial.³⁷ Overall survival was significantly longer in the sipuleucel-T group than the placebo group (25.8 months vs. 21.7 months, respectively; hazard ratio, 0.78; 95% CI, 0.62–0.98), although objective time to disease progression was similar between the 2 groups (14.6 weeks vs. 14.4 weeks, respectively). Treatment effects on QOL outcomes were not reported.

Sipuleucel-T is currently only recommended for use in patients with asymptomatic or minimally symptomatic mCRPC, based on the patient population included in the clinical trials of the drug. The costs associated with sipuleucel-T are substantial and must be considered when considering treatment with the therapy.

Sipuleucel-T is administered as a 1-hour intravenous infusion every 2 weeks for a total of 3 doses. Patients may only be treated by registered prescribers and at participating sites. Premedication with acetaminophen and an antihistamine is recommended to prevent infusion-related reactions. Common side effects associated with sipuleucel-T include chills, fevers, fatigue, nausea, and pain.⁸

Summary and perspective

ADT is considered the first-line pharmacologic treatment for patients with advanced or metastatic prostate cancer. However, over time, a portion of these patients may develop diminishing or no effect from ADT, resulting in CRPC. The treatment of mCRPC historically has been challenging, with few therapeutic successes. In just the past few years, however, 4 new agents have been approved for the treatment of patients with mCRPC. Clinicians now have a multitude of effective agents to choose from, but an absence of published data from head-to-head clinical trials of these newer agents. Several guidelines have recently been published to address therapeutic decisions in the setting of mCRPC.^4,38,39,40

Four agents have been approved for use in patients with previously untreated mCRPC: docetaxel, sipuleucel-T, abiraterone and enzalutamide. All have been shown to prolong overall survival, but only docetaxel, abiraterone and enzalutamide have been reported to improve QOL outcomes as well. With a lack of clinical trials demonstrating the superiority of one agent over the other, choice of therapy may be guided by the patient population in which the agents have demonstrated activity and the very different side-effect profiles of the 4 agents (Table 3).

The American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) clinical practice guidelines favor the use of either abiraterone or enzalutamide in patients with previously untreated mCRPC based on a more favorable benefit-risk profile, as compared to docetaxel, and on the absence of QOL data for sipuleucel-T.⁴⁰ The NCCN guidelines, however, consider the presence or absence of symptoms and visceral metastases in their recommendations, with docetaxel preferred over enzalutamide for patients with symptomatic disease or visceral metastases, and abiraterone or enzalutamide preferred for patients with asymptomatic disease.⁴ The American Urological Association guidelines were updated before the approval of enzalutamide as a first-line treatment option for patients with mCRPC.^38,39

Although the FDA labeling for many of the newer agents approved for mCRPC define the usage for these agents in patients who either have or have not received prior therapy with docetaxel, the previously accepted first-line therapy for most patients with mCRPC, some experts assert that this distinction is currently of limited clinical usefulness.⁴⁰ Indeed, as more patients with mCRPC receive first-line therapy with either abiraterone or enzalutamide, it will become important to determine the most appropriate second-line therapy after treatment with either abiraterone or enzalutamide.

NEXT: References

For those patients with mCRPC who received first-line therapy with docetaxel and progressed, 4 treatment options exist that have been shown to improve overall survival: abiraterone, enzalutamide, cabazitaxel and sipuleucel-T. Both abiraterone and enzalutamide have been shown to improve QOL outcomes as well, while cabazitaxel and sipuleucel-T have been shown to improve overall survival only.^20,24,34,37 Unlike cabazitaxel, sipuleucel-T has only been investigated in patients without visceral metastases.

Although several non-cytotoxic chemotherapy options have become available for the treatment of patients with mCRPC, the optimal treatment of patients with nonmetastatic CPRC remains unclear. Published results of abiraterone and enzalutamide in this patient population are eagerly awaited. In addition, combination therapy with abiraterone plus enzalutamide could represent another potential treatment option in patients with mCRPC, pending the results of published clinical trials.

New chemotherapeutic drugs targeting new pathways, such as matrix metalloproteinase inhibitors, antiangiogenesis agents, and growth factor inhibitors, may provide alternative treatments for prostate cancer. The development of useful agents that can reverse multidrug resistance and resensitize cancer cells to cytotoxic agents could remarkably improve the therapeutic outcome in patients with chemotherapy-resistant prostate cancer. Immunotherapy using prostate-cancer‒specific antibodies or vaccines could be another promising treatment for prostate cancer, including advanced or recurrent forms of the disease.

With ongoing developments in genomic and biological technology, the specific mechanisms related to prostate carcinogenesis will be more thoroughly dissected, which will pave the way for targeted, more effective therapies for patients with prostate cancer in the future.

References

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Drs Wang and Chow are with the Center for Advancement of Drug Research, College of Pharmacy, Western University of Health Sciences, Pomona, California. Dr Pon is in the department of pharmacy practice and administration, College of Pharmacy, Western University of Health Sciences and Department of Pharmacy, City of Hope National Medical Center, Duarte, California.

Disclosures: The authors have no relevant conflicts of interest related to the topic of this review.