New Therapies for Prostate Cancer: The Practicalities

Scanning electron color-enhanced image depicts prostate cancer cells.

Photo courtesy Annie Cavanagh/Cell Image Library

Unlike other cancers, the treatment options for prostate cancer have remained fairly consistent over the last decade. Research has been stymied by the bland molecular sub-characterization of prostate cancer in contrast to other cancers. For example, breast cancers may or may not express hormone receptors, and various expressions are strongly linked to response. Prostate tumors—all of them—have androgen receptors. All first-line treatments have been androgen-directed, especially initially.

Urologists and oncologists have had several treatment protocols to choose from, all approximately the same in terms of overall efficacy, although patient response has been variable. The general treatment steps have been androgen deprivation, second-line hormonal manipulations, and chemotherapy. Throughout, bone health has been a concern.

Now, with four new agents approved in the last two years (Table) and two promising agents in the pipeline, therapy selection and potential outcomes are changing.

Oliver Sartor, MD

Each of the four newest therapies has been proven to improve overall survival or to delay skeletal-related events better than the standard therapies available prior to their approval. According to Oliver Sartor, MD, Laborde Professor for Cancer Research and medical director at the Tulane Cancer Center, New Orleans, Louisiana, “Urologists make strong bonds with their patients, and often follow them for years. All of these agents will be useful to urologists, although they may prefer to have patients with advanced disease treated in the medical oncology setting.”

Available Now

Sipuleucel-T

This autologous cellular immunotherapy induces an immune response targeted against an antigen expressed in 95% of prostate cancers, prostatic acid phosphatase (PAP). The FDA approved its use for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC).^1,2

Sipuleucel-T offers a new option—immunotherapy— between initial androgen deprivation and second-line hormone manipulation. Using multiple agents to attack different parts of the neoplasm’s growth cycle is a general approach in most cancers. The sipuleucel-T trials enrolled patients who were either taxane-naïve or who had been treated with a taxane, but were fairly robust. To enroll, patients had to have no or minimal cancer symptoms, no visceral metastases, no regular opioid use, good performance status and organ function, and a washout of three months after prior cytotoxic therapy. Patients who are in earlier stages of disease and fail androgen-deprivation therapy (ADT) possess better innate immunity, which is needed to mount an immune response to this “vaccine.” More robust responses increase the likelihood of extended survival.^2,3-5

Table. New and Investigational Therapies for Prostate Cancer

Drug Name

Brand Name/Approval

Mechanism of Action

Sipuleucel-T

Provenge, approved April 29, 2010

An autologous cellular immunotherapy that targets PAP

Denosumab

Xgeva, approved June 1, 2010

A monoclonal antibody that binds to RANK ligand, decreasing bone resorption and increasing bone mass and bone strength

Cabazitaxel

Jevtana, approved June 17, 2010

A semi-synthetic taxane developed to overcome taxane resistance

Abiraterone acetate

Zytiga, approved April 28, 2011

An oral second-generation androgen synthesis-inhibitor that targets the dual-enzyme complex CYP17

MDV3100

Investigational, Medivation, Inc.

An irreversible androgen receptor antagonist and androgen receptor signaling inhibitor

Radium-223 chloride

Investigational, Ra-223 or Alpharadin, Bayer HealthCare

Delivers alpha-particle radiation to the bone and prostate cancer bone metastases

PAP indicates prostatic and phosphatase.

Many urologists are administering sipuleucel-T in the office, an approach that requires good planning and communication with patients. Patients undergo a leukapheresis procedure approximately three days before receiving each sipuleucel-T infusion. Urologists need to stress to patients that punctuality for the leukapheresis procedure and office infusion is essential, since leukapheresis and infusions must be appropriately spaced and sipuleucel-T expires quickly. Patients receive three doses at approximately two-week intervals.^3-5

Sipuleucel-T is well tolerated. The most common adverse reactions, reported in up to 15% of patients, include back pain, chills, fatigue, fever, headache, joint ache, and nausea. Most patients report these as mild or moderate in severity, and most reactions occur within a day of infusion and resolve within two days. Approximately one-quarter of patients experience serious adverse reactions, defined as grade 3 or greater; these include acute infusion reactions and cerebrovascular events. Several notable single-case reports (eosinophilia, myasthenia gravis, myositis, rhabdomyolysis, and tumor flare) have been reported. ^3-5

Denosumab

This monoclonal antibody binds to RANK ligand, a protein essential for osteoclast formation, function, and survival. Denosumab decreases bone resorption and increases bone mass and bone strength. It is FDA-approved for two indications: to increase bone mass in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer who are at high risk for fracture, and for prevention of skeletal-related events in patients with bone metastases from solid tumors.⁶

In these patients, denosumab also reduced the incidence of vertebral fractures. Between 50% and 60% of patients with CRPC currently receive a bisphosphonate. Denosumab is a superior osteoclast inhibitor compared with the current standard for patients with bone metastases, zoledronic acid (Zometa).⁷ According to Emmanuel Antonarakis, MBBCh, assistant professor of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland, “Xgeva [denosumab] is given subcutaneously and doesn’t require creatinine monitoring, so it’s somewhat easier to use than Zometa. It can be administered with ease in outpatient settings.”

The most common adverse reactions reported for denosumab include back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. Serious adverse reactions are possible and include hypocalcemia, serious infection, skin rash and dermatitis, osteonecrosis of the jaw, and pancreatitis. Calcium and vitamin D supplementation is essential, and urologists need to counsel patients carefully about seeking prompt medical attention if they develop signs or symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps.^6,7

After Docetaxel

Cabazitaxel

This semi-synthetic taxane was developed to overcome taxane resistance. Compared to mitoxantrone, cabazitaxel significantly improved survival in patients with metastatic CRPC who had previously received docetaxel. Mortality on this agent is approximately 5%, however.⁸

The FDA approved cabazitaxel in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel regimen. Dosage is individualized based on body surface area (25 mg/m2) every three weeks. Cabazitaxel requires dose adjustments in hepatic impairment.⁸

Abiraterone Acetate

This oral second-generation androgen-synthesis inhibitor targets the dual-enzyme complex CYP17. Some experts call it a “better ketoconazole” due to its more specific and potent androgen suppression. It has been FDA-approved in combination with prednisone for metastatic CRPC patients who have received prior docetaxel. Abiraterone severely inhibits testosterone production by the adrenal gland and in the tumor itself. However, it also increases mineralocorticoid production, creating the need to administer it together with prednisone to abrogate the clinical effects of mineralocorticoid excess. In the pivotal clinical trial for abiraterone, patients treated with abiraterone acetate/prednisone lived a median of 14.8 months compared with 10.9 months for placebo/prednisone.^9,10

Abiraterone is usually given as a 1000-mg once-daily dose in combination with prednisone 5 mg twice daily to ameliorate hypertension and hypokalemia. Patients receiving GnRH agonists must remain on them for the entire course of treatment with abiraterone and prednisone. Periodic liver function monitoring is needed.¹¹

Abiraterone is approved for use in patients previously treated with docetaxel, but recent findings in chemotherapy-naïve patients have been positive. COU-AA-302, a large (N >1000) phase III trial of abiraterone/ prednisone versus placebo/prednisone in chemotherapynaïve patients, was unblinded in March 2012 because of the positive trend toward response in the abiraterone group. An analysis of interim evidence found that abiraterone/prednisone effectively treated mildly symptomatic or asymptomatic metastatic CRPC patients who had not gone through chemotherapy. The most common adverse events were hypertension, fluid retention, hypokalemia, and cardiac events, although there were no significant differences in grade 3-4 events in the treatment-versus-placebo group.^12,13

Promising Pipeline

MDV3100

Radium-223 chloride

This investigational agent is an irreversible androgen receptor (AR) antagonist and AR signaling inhibitor, and represents an advance from the nonsteroidal AR antagonists flutamide, bicalutamide, and nilutamide. MDV3100 has redundant mechanisms: It blocks testosterone binding to the AR, impedes the movement of the AR to the nucleus of prostate cancer cells, and inhibits binding to DNA.¹⁴ In November 2011, the data and safety monitoring committee unblinded Medivation’s phase III AFFIRM trial when a planned interim analysis revealed that the estimated median survival was 18.4 months in MDV3100-treated patients compared with 13.6 months for placebo-treated patients. In addition to this 37% reduction in risk of death with MDV3100, the drug also caused tumor shrinkage in approximately 30% of patients and a 50% decline in prostate-specific antigen level.

This drug delivers radiation to the bone and prostate cancer bone metastases. In a phase III clinical trial conducted in men with bone-metastatic CRPC who were docetaxel-refractory or docetaxelineligible, Ra-223 improved patient survival by an average of three months. In addition, Ra-223 drug therapy delayed bone damage or the need for surgery or radiation by more than five months.^15-18

Practicalities of Treatment

As new agents emerge and offer promising results, one concern that has arisen is cost, especially in the freestanding urology practice. “Some of these agents are extremely costly, and practices will need to plan ahead and work with both the drug companies and insurers to make sure that their cash flow is protected,” Sartor said. “And dosing needs to be scheduled carefully—a practice can lose thousands of dollars when even one dose is wasted.”

The availability of several new treatment options for advanced CRPC presents urologists and their patients with another dilemma: Sometimes, clinical evidence may be insufficient to make informed decisions. One example is a case in which a patient with advanced disease no longer responds to standard hormonal therapies but has not been treated with docetaxel. Some physicians might want to use abiraterone, given current early evidence that this type of patient might respond to abiraterone, but the therapy has not yet been approved for use in this setting. This type of off-label use may not be covered by insurance. Approval of earlier use of abiraterone may depend upon the recently unblinded COU-AA-302 study. If and when that happens, however, physicians will then have the choice of whether to use sipuleucel-T or abiraterone first, or whether the two agents can be safely combined.

In addition, noted Antonarakis, urologists who use these new agents will need to pay attention not only to dosing and side effects, but also to drug interactions. “Although the FDA has approved these new therapies for very specific indications, we can expect them to be used earlier in the disease as new data emerge. In addition, ongoing clinical trials will eventually identify new combinations of these drugs. For example, while only single-agent trials using Radium-223 have been completed thus far, a phase I study using Radium-223 in combination with docetaxel is now recruiting,” Antonarakis said. Experts believe that novel sequencing of treatments may improve survival rates for men with metastatic CRPC over the next few years. The optimal sequencing is being studied, and several studies are under way or being planned that examine concurrent or sequential use of novel agents with older therapies or with each other.

References

1. Provenge [package insert]. Seattle, WA: Dendreon Corporation; April 2010.
2. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castrationresistant prostate cancer. N Engl J Med. 2010;363:411-422.
3. Provenge [package insert]. Seattle, WA: Dendreon Corporation; April 2010.
4. Beinart G, Rini BI, Weinberg V, Small EJ. Antigen-presenting cells 8015 (Provenge) in patients with androgen-dependent, biochemically relapsed prostate cancer. Clin Prostate Cancer. 2005;4:55-60.
5. Rini BI, Weinberg V, Fong L, Conry S, Hershberg RM, Small EJ. Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (Provenge ) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy. Cancer. 2006;107:67-74.
6. Xgeva [package insert]. Thousand Oaks, CA: Amgen Inc; November 2010.
7. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813-822.
8. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154.
9. Scher HI, Logothetis C, Molina A, et al. Improved survival outcomes in clinically relevant patient subgroups from COUAA- 301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel-based chemotherapy. J Clin Oncol. 2011;29(suppl; abstr 4).
10. Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration- resistant prostate cancer. J Clin Oncol. 2010;28:1496-1501.
11. Zytiga [package insert]. Toronto, Canada: Pantheon; April 2011.
12. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castrationresistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:1437-1446.
13. [No author.] J&J unblind Zytiga phase 3 trial in pre-chemotherapy castrate-resistant prostate cancer. March 8, 2012. Available at http://pharmastrategyblog.com/2012/03/jj-unblind-zytiga-phase-3-trial-in-pre-chemotherapy-castrate-resistant-prostate-cancer.html. Accessed April 2, 2012.
14. Safety and Efficacy Study of MDV3100 in Patients With Castration-Resistant Prostate Cancer Who Have Been Previously Treated With Docetaxel-based Chemotherapy (AFFIRM). 2009. Available at: http://clinicaltrials.gov/ct2/show/NCT00974311.Accessed March 17, 2012.
15. Nilsson S, Strang P, Aksnes AK, et al. A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer. 2012;48(5):678-686.
16. [No author.] Radium-223 plus chemo shows clear OS benefit. Oncology (Williston Park). 2011;25:1232, 1234.
17. Nilsson S, Franzén L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587-594.
18. Parker C, Heinrich D, O’Sullivan JM, et al. Overall survival benefit and safety profile of radium-223 chloride, a first-in-class alpha-pharmaceutical: results from a phase III randomized trial (ALSYMPCA) in patients with castration-resistant prostate cancer (CRPC) with bone metastases. J Clin Oncol. 2012 (suppl 5; abstr 8 ). Available at http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=116&abstractID=89142. Accessed April 2, 2012.