On April 28, 2011, the US Food and Drug Administration (FDA) approved abiraterone acetate (Zytiga, Johnson & Johnson) for the treatment of metastatic castration-resistant prostate cancer (CRPC) for patients who have failed docetaxel therapy. Prostate cancer is a leading cause of cancer mortality and morbidity in the United States.1,2 Each year approximately 215,000 men are diagnosed and 32,000 men die of the disease. Androgen ablation is the cornerstone for the treatment of metastatic prostate cancer, as a result of Huggins and Hodges’ Nobel Prize–winning work published in 1941. Depletion of circulating androgens either through surgical or medical castration is the first therapeutic maneuver for men failing definitive therapy (radical prostatectomy or external beam radiation). For several decades it was believed that the progression following androgen-deprivation therapy (ADT) was resistant to further hormonal manipulations.3 This paradigm started to change when prostate cancer gene–expression studies found that androgen-receptor–activated genes, which are normally downregulated during ADT, become reactivated on transition to CRPC.4,5 Furthermore, ADT strategies resulted in castrate concentrations of testosterone; however, it was found that low levels of circulating androgen persisted (mainly through peripheral conversion of adrenal steroids). In addition, gene upregulation is involved in androgen biosynthesis, including CYP 17.6-8 Intratumoral enzymes involved in the conversion of upstream precursors of testosterone and dihydrotestosterone became a molecular target. Clinical Trials Cytochrome p450c17 is involved in androgen biosynthesis by 17-alphahydroxylation of C21 steroids and cleavage of C17,20 bond of C21 steroids.3,9 These reactions are critical in the biosynthesis of dehydroepiandro - sterone and androstenedione. Abirate rone is a potent, selective, irreversible inhibitor of CYP 17A1.10 In the initial phase 1 trial of abiraterone conducted in chemotherapy-naïve CRPC patients, the drug was well tolerated. The dose (1000 mg/day) used in the phase 2 trial was determined after a plateau in the pharmacodynamic effects was observed. When compared with baseline values during an additional phase 1/2 trial of abiraterone in chemotherapy-naïve patients, 67% of the patients achieved a decline in prostate-specific antigen (PSA) ≥50% and the median time to PSA progression (TTPP) on abira - terone alone for all phase 2 patients was 225 days.11 Toxicities observed were attributed to changes in mineralocorticoid, which were manageable with lowdose corticosteroids.11,12 The pivotal trial for abiraterone was conducted in the postchemotherapy setting for men with CRPC. In COUAA- 301, a large randomized, double-blind, placebo-controlled phase 3 study, chemotherapy-refractory meta - static patients were treated with either abiraterone plus low-dose prednisone (n = 797) or prednisone plus placebo (n = 398). The median overall survival, the primary end point for this study, was 15.8 months and 11.2 months, respectively, after 775 events (hazard ratio, 0.740; 95% confidence interval, 0.638-0.859), and the benefit was observed across multiple subgroups, such as performance status, sites of metastatic disease, and number of previous chemotherapy regimens received. Other trial end points, including PSA change, TTPP, and radiographic progression- free survival (PFS), also resulted in superior outcomes. Patients on abir - aterone achieved a PSA decline of >50% in 38% of the patients compared with 10% for placebo (P <.0001), had a significant delay in TTPP (10.2 vs 6.6 months, P <.0001), and radiographic PFS (5.6 vs 3.6 months, P <.0001). Although the incidence of adverse events was higher in patients receiving placebo, there were more patients who experienced grade 3 and 4 toxicities on the treatment arm (fluid retention, hypo kalemia, and hypertension).13 An Additional Option Treatment options for men with CRPC are limited, but abiraterone/prednisone is a welcomed addition to the armamentarium. With this addition, we now have 5 FDA-approved regimens for the treatment of this disease (sipuleucel-T, docetaxel plus prednisone, cabazitaxel plus prednisone, and mitoxantrone plus prednisone). The real question is whether clinicians will move this treatment to the prechemo therapy setting. Abiraterone is a novel agent that inhibits androgen synthesis by selectively blocking CYP 17. The role of prednisone is of some concern, especially with prolonged use. None theless, this is a true example of translating basic laboratory observations into clinic advances. References
By Gary Shelton, MSN, NP, ANP-BC, AOCNP Oncology Clinical Nurse Specialist and Adult Nurse Practitioner, New York University Cancer Institute, New York, New York
With the addition of abiraterone acetate as a treatment option for metastatic castration-resistant prostate cancer (CRPC), healthcare providers have more to talk about when planning or outlining management strategies for men as they progress through hormonal ablations and beyond. For men with prostate cancer, they now have more to think about when sitting before us, as we discuss treatments. Abiraterone has been in the press and on the tongue of patients’ questions for a number of months and now will require concentrated efforts, such as discussing the approval profile and the appropriate population of men for whom the US Food and Drug Admin - istration has approved this new compound. Whether we have taken part in clinical trials offering abiraterone or responding to patients’ requests of compassionate use of abiraterone, this oral agent has been anticipated with great interest from all fronts. Depleting circulating androgens with various hormonal manipulations has been the mainstay of treatment, after curative efforts have failed or been unreachable. And although these medications have all come with a cost, men generally have ac cepted the side effects and alterations with their masculinity/ sexuality due, in large part, to the ease of taking oral medication. Although as healthcare providers, we may debate these merits, patients have been generally more accepting of therapies that can be held than those requiring giving up an arm and a vein for infusions. Abiraterone acetate is, therefore, an attractive addition to treatment options, and creates a new niche or an opportunity for an oral intervention in a new setting, for men with CRPC. Always welcoming of educational opportunities, we now are aware of changes in the androgen receptor milieu that can be reactivated after prostate cancer cells become castration resistant. Abiraterone acetate is a potent inhibitor, both selective and irreversible, of CYP 17, the enzyme responsible for androgen biosynthesis. This enzyme is expressed in testicles, in adrenals, and within prostate cancer tumor tissue. Abiraterone, therefore, can be effective even with chemical or surgical castration. As with all oral therapies, patients are on their own to be compliant, making proper patient selection key to efficacy and identification of tolerability. Abiraterone is taken on an empty stomach because of its affinity to protein binding. Instruct men to wait at least 1 hour after taking this medication before eating. Also impress upon patients the importance of waiting at least 2 hours after eating before swallowing abiraterone. Men also should understand that their dosing (approved at four 250- mg tablets) needs to be taken with a large glass of water. The current approval and treatment indication of abiraterone acetate is for use in combination with prednisone, for the treatment of patients with metastatic CRPC who have failed prior chemotherapy containing docetaxel. Although abiraterone has been/is being investigated in both postchemotherapy and the chemotherapy-naïve populations, this initial indication is specific to docetaxel failures. As is common in practice settings, men wish to hold off on starting chemotherapy regimens until all oral options have been exhausted. Until study data mature from the chemotherapy-naïve populations, there is no label use of abiraterone in the prechemothearapy arena. Patients unready for chemotherapy already are calling for prescriptions. For now, we educate and offer options based on the evidence, and label; don’t we?
To sign up for our newsletter or print publications, please enter your contact information below.
