Abiraterone Acetate: Expanded Indication for Metastatic Prostate Cancer

TON - May 2013, Vol 6, No 4 — May 28, 2013

Abiraterone acetate is a novel antiandrogen agent that has recently received an expanded indication for treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Prostate cancer remains the most common noncutaneous malignancy, accounting for 28% of all cancers, among American men. According to the American Cancer Society’s estimates, about 238,590 new cases of prostate cancer will be diagnosed and approximately 29,720 men will die of the disease in 2013.1

A growing number of drugs have been developed for the treatment of advanced mCRPC since docetaxel was first approved when it indicated a survival advantage.2 The rapidly emerging field of prostate cancer therapeutics is dramatically changing the mCRPC treatment landscape. With the advent of new medications using different mechanisms of action, options for treatment are becoming more varied and include hormones, intravenous (IV) chemotherapy, and novel agents such as abiraterone acetate. It is imperative that oncology nurses be aware of these multiple treatment options to provide proper care for their patients.

Concomitantly with prednisone, abiraterone acetate attained approval from the US Food and Drug Administration (FDA) in April 2011 for the treatment of mCRPC after docetaxel failure, based on the results of the phase 3 COU-AA-301 trial.3 Those findings indicated that overall survival (OS) was longer in the abir-aterone acetate/prednisone group. In 2012, the FDA approved an expanded indication for abiraterone acetate in combination with prednisone,4 the significance of which is that it allowed patients with mCRPC to be treated with this oral agent prior to receiving IV chemotherapy.

Hormones
Advanced prostate cancer has been treated by depleting or blocking the action of androgens. This results in a decrease in the concentration of prostate-specific antigen (PSA) as well as tumor regression and relief of symptoms. Frequently, these responses do not continue and the disease progresses.5 Secondary hormonal options or chemotherapy may be used when prostate cancer no longer responds to hormone therapy alone. Because androgen receptor activation and autocrine/paracrine synthesis are potential mechanisms of cancer recurrence during androgen deprivation therapy, castrate levels of testosterone should be maintained while additional therapies are employed.6

The androgen signaling pathway remains important throughout the course of mCRPC. Hormone-refractory (or hormone-resistant) prostate cancer is an imprecise description of metastatic disease that has progressed despite castrate levels of serum testosterone. Clinical evidence suggests that tumors may remain hormone sensitive.7 There are multiple mechanisms by which tumor cells adapt to a low-androgen environment.8

Prostate cancer tumor cells have enzymatic pathways that produce their own androgen supply. Tumor tissue androgen levels in mCRPC remain sufficient to activate the androgen receptor despite primary androgen-deprivation therapy (surgical or medical castration).9,10 In mCRPC, the tumor may become hypersensitive to even small amounts of androgen.11

Mechanisms of Action
Abiraterone acetate is a selective inhibitor of androgen biosynthesis that potently blocks cytochrome P450 c17 (CYP17). Consequently, androgen biosynthesis is inhibited at 3 sources of testosterone production: the testes, adrenal glands, and prostate tumor tissue.3 Androgen-deprivation therapies, such as gonadotropin-releasing hormone (GnRH) analogs or orchiectomy, lower androgen production. This occurs in the testes but not in adrenal glands or in tumors.12

Recent COU-AA-302 Study
The most recent approved indication for abiraterone acetate was in combination with prednisone for patients with mCRPC. The approval was based on a trial, COU-AA-302, of 1088 men with mCRPC who had not received cytotoxic chemotherapy and were asymptomatic or mildly symptomatic. Participants were randomized to receive either abiraterone acetate plus prednisone (n = 546) or placebo plus prednisone (n = 542). Entry was restricted to those with metastasis to the bone, soft tissue, or lymph nodes. Patients were excluded if they had liver metastases, had moderate to severe pain, or if their aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) was ≥2.5 x the upper limit of normal. All patients had either a previous orchiectomy or continued to receive GnRH analog.4

OS and radiographic progression-free survival (rPFS) were the coprimary end points of the study. Compared with placebo, treatment with abiraterone acetate improved rPFS: median rPFS was 8.3 months for those in the placebo arm and had not yet been reached for those receiving abiraterone acetate (hazard ratio = 0.43; 95% CI, 0.35-0.52; P <.0001). At the prespecified third interim analysis, median OS was 35.3 months in the abiraterone acetate arm and 30.1 months in the placebo arm. Significant improvements in time-to-opiate use and time-to-cytotoxic chemotherapy supported the primary end points.4

Adverse Effects
Safety data were evaluated in the 2 pivotal trials of the 1333 men with mCRPC who received abiraterone acetate plus prednisone and the 934 men who received placebo plus prednisone. Fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion were the most commonly reported adverse reactions (≥10%). Anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST and ALT, hypophosphatemia, and hypokalemia were the most commonly observed laboratory abnormalities (>20%).4

In 55% of patients receiving abiraterone acetate and in 50% of patients receiving placebo, grade 3/4 adverse reactions occurred. There were grade 3/4 increases in ALT or AST in 4% of patients in the abir-aterone acetate arm. Grade 3/4 cardiac failure occurred more frequently in patients receiving abiraterone acetate (1.6%) compared with those receiving placebo (0.2%). Adrenal insufficiency occurred in 0.5% and 0.2% of patients receiving abiraterone acetate or placebo, respectively.4

Coadministration of prednisone reduces the incidence and severity of mineralocorticoid-related adverse reactions (hypokalemia, hypertension, and fluid retention). Secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland drives the production of mineralocorticoids, androgens, and glucocorticoids such as cortisone. Treatment with abiraterone acetate inhibits the production of cortisone and androgens as a result of CYP17 inhibition. Through the negative feedback mechanism, secreted levels of ACTH increase in response to a decrease in circulating cortisone level. There is a corresponding increase in mineralocorticoid levels that may lead to these adverse reactions.13,14

Prednisone 5 mg orally twice daily in combination with abiraterone acetate preempts the activation of the negative feedback mechanism, because the system no longer perceives a net cortisol deficit.15

Contraindications
Oncology nurses should be familiar with important adverse effects of the medication. Pregnancy is a contraindication for abiraterone acetate, as it may cause fetal harm (Pregnancy Category X).12,16 If the patient’s sexual partner may become pregnant, a condom and another form of birth control must be used. Pregnant women and those of childbearing potential should not handle the medication without protection.16

Mineralocorticoid-Related Adverse Reactions
There is a risk of mineralocorticoid excess, and the medication must be used with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. Safety has not been established in patients with left ventricular ejection fraction <50%, New York Heart Association Class III or IV heart failure, or recent myocardial infarction. It is also recommended that hypertension be controlled and hypokalemia be corrected before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. Adrenocortical insufficiency has been reported after an interruption of daily steroids and/or with concurrent infection or stress.12

Hepatotoxicity
Hepatotoxicity can occur; increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue the drug as necessary. Monitor liver function enzymes prior to starting treatment, every 2 weeks for the first 3 months, and monthly thereafter.12

Drug Interactions
Because abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6, drug interactions may occur. Coadministration with CYP2D6 substrates that have a narrow therapeutic index (eg, thiorid- azine) should be avoided. Note that this drug potentiates dextromethor- phan. Strong inhibitors and inducers of CYP3A4 should be avoided or be used with caution.12

Dosing
The dosage for abiraterone acetate is 1000 mg (four 250 mg tablets) administered orally once daily on an empty stomach. Exposure increases are 10- to 17-fold higher when administered with a meal compared with a fasting state. Tablets should be swallowed whole with water; patients should not crush or chew tablets. Be aware that many patients will try to take one tablet 4 times a day rather than all the abiraterone acetate at once. Note that abiraterone acetate is used in combination with prednisone 5 mg orally twice daily.12 Prednisone helps reduce the incidence and severity of mineralocorticoid-related adverse reactions.

Adherence
In recent years, the term “compliance” has been replaced by “adherence,” a less judgmental expression that refers to how consistently a patient takes a medication exactly as prescribed.17 Adherence to oral agents is critical to their success. Issues related to adherence include limited insurance coverage, comorbid conditions, polypharmacy, and understanding the treatment regimen.

The increased use of oral agents requires that oncology nurses assess and measure patient adherence. This can be achieved by evaluating the percentage of medications taken, the duration that they are taken, and the timing of medication. Tools to assist with medication adherence include alarm clocks, talking pill bottles, reminder phone calls, medication diaries, online patient portals, and web chats. In addition, medical record audits can be successful.18 Reasons that have been given for poor adherence include cost, forgetfulness, anxiety, denial, illiteracy, complexity of the regimen, and trouble swallowing pills.19

Conclusions
Abiraterone acetate is now approved for use in patients with mCRPC, prior to docetaxel treatment. To provide the best care for patients with cancer, oncology nurses must know the uses and benefits, as well as the adverse effects, of this novel therapy.

References
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2. El-Amm J, Aragon-Ching JB. The changing landscape in the treatment of metastatic castration-resistant prostate cancer. Adv Med Oncol. 2013;5(1):25-40.
3. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.
4. US Food and Drug Administration. Abiraterone acetate. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm331628.htm. Updated December 11, 2012. Accessed March 10, 2013.
5. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23(32):8253-8261.
6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prostate Cancer. Version 2.2013. http://www.nccn.org/professionals/physician_gls/f_guide lines.asp. Accessed April 23, 2013.
7. Scher HI, Steineck G, Kelly WK. Hormone-refractory (D3) prostate cancer: refining the concept. Urology. 1995;46(2):142-148.
8. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol. 2009;10(10):981-991.
9. Titus MA, Schell MJ, Lih FB, et al. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657.
10. Mohler JL, Gregory CW, Ford OH III, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10(2):440-448.
11. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):6407-6415.
12. Zytiga (package insert). Horsham, PA: Centocor Ortho Biotech Inc. December 2012.
13. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am. 2001;30(1):101-119.
14. Janssen Biotech. Zytiga (abirateron acetate) tablets dosing and administration guide for healthcare professionals. Zytiga. http://www.zytigahcp.com/dos age-and-administration. Accessed May 13, 2013.
15. Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 2005;96(9):1241-1246.
16. Chemotherapy Advisor. Zytiga Rx. http://www.chemotherapyadvisor.com/zytiga/drug/7009. Accessed April 23, 2013.
17. Gangloff JM. Troubling trend: medication adherence. Cure. 2013;(spring suppl):4-8. http://www.cure today.com/index.cfm/fuseaction/article.show/id/2/arti cle_id/2061. Accessed April 23, 2013.
18. Spoelstra SL, Given CW. Assessment and measurement of adherence to oral neoplastic agents. Semin Oncol Nurs. 2011;27(2):116-132.
19. Vaughn D. Taking charge of your cancer treatment. Cure. 2013;(spring suppl):10-15. http://www.curetoday.com/index.cfm/fuseaction/article.show/id/2/article_id/2062. Accessed April 23, 2013.

Patient Clinical Case

A 70-year-old man had a history of prostate cancer that was originally diagnosed in 1997. He initially was treated with surgery, then required radiation therapy to the prostate bed. He had a rising PSA and was treated with intermittent hormones and triptorelin (Trelstar). In 2010, he developed bone metastasis with activity seen on bone scan. His PSA rapidly climbed to 37. He was again placed on triptorelin and was briefly on bicalutamide, with PSA continuing to climb. Bicalutamide was discontinued and PSA continued to increase. At this point he required additional treatment. However, in February 2011, abiraterone acetate was not indicated before chemotherapy. He therefore was started on docetaxel. He had a rapid decline in performance status, developed severe asthenia, and was also hospitalized for pneumonia. After 3 cycles, his PSA decreased but docetaxel had to be discontinued because of adverse effects. While off the docetaxel, his PSA quickly doubled and he elected to proceed with abiraterone acetate. At initiation of the medication in May 2011, his PSA was 35, and quickly dropped to 0.7 by July 2011. Within a few weeks, his performance status returned to baseline, his pain improved, and he returned to his active lifestyle. The patient has continued on abiraterone acetate, in addition to triptorelin and monthly zoledronic acid. The plan is to continue the current regimen. 

This clinical case is an excellent example of the benefits of abiraterone acetate. With the latest approval for abir-aterone acetate, patients can be afforded the opportunity to receive this treatment before chemotherapy. 

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