For patients with metastatic disease, the median overall survival (OS), until very recently, had been less than 2 years after chemotherapy.

While tumor progression with ADT was previously believed to be hormone-refractory or androgen-independent, a large body of evidence supports that metastatic castration-resistant prostate cancer (mCRPC) is commonly driven by elevated steroid synthesis, increased expression or splice variants of the androgen receptor (AR), or AR ligand promiscuity, indicating the ongoing need for targeted androgen therapies.

Abiraterone acetate (AA), the prodrug of abiraterone, alone or in combination with low-dose steroids, has been intensely investigated in recent years for the treatment of progressive CRPC in patients who have received prior chemotherapy or who were treatment-naive. Abiraterone is a selective and potent inhibitor of cytochrome P450 c17 (CYP17), an enzyme that is critical for testosterone synthesis in the adrenal glands.

Long-Term Analysis of Abiraterone Plus Prednisone

Despite the established clinical utility of steroids in mCRPC and other tumor types to manage adverse events (AEs) of chemotherapy and cancer-associated pain, long-term use of high doses of glucocorticoids, such as prednisone, have a number of associated AEs. As such, an analysis of the frequency and severity of AEs in patients treated with long-term dosing of AA and prednisone is of interest.

Data sets from the COU-AA-301 and COU-AA-302 phase III clinical trials were used to determine whether long-term use of low-dose prednisone with or without AA would lead to significant AEs in patients with mCRPC. Karim Fizazi, MD, PhD, from the Institut Gustave Roussy in Villejuif, France, and colleagues reported their findings in the March 7, 2016, issue of European Urology.

Investigators analyzed AEs in 1195 patients from the COUAA-301 trial and 1088 patients from the COU-AA-302 trial. All patients received prednisone 5 mg twice daily for a median of 8.3 months. Investigators utilized the Standardized MedDRA Queries to identify preferred terms known for glucocorticoidassociated AEs.

For all patients, those treated with AA and prednisone (AA + P), and those treated with prednisone alone (P alone), the overall incidence of any-grade AEs for any prednisone exposure was 24.6%, 25.5%, and 23.3%, respectively. The most common any-grade AEs were hyperglycemia (7.4%, 7.8%, and 6.9% for all patients, those treated with AA + P, and those treated with P alone, respectively) and weight increase (4.3%, 3.9%, and 4.8%, respectively). Among any-grade AEs, ecchymosis, rib fracture, Cushingoid state, cataract, diabetes mellitus, and skin atrophy occurred at rates &ge;1%. The incidence of grade &ge;3 AEs for any prednisone exposure was 4.5%, 5.1%, and 3.7% for all patients, AA + P, and P alone, respectively. Hyperglycemia (48%) and cataract (10%) were the 2 most common grade &ge;3 AEs. No discernable trends were observed in any-grade or grade &ge;3 AEs when examined by duration of exposure.

These results indicate that treatment with low-dose prednisone, administered with or without AA, is associated with few glucocorticoid-related AEs, and that the incidence of AEs is not directly related to prednisone exposure duration. As such, long-term treatment with AA plus prednisone is safe and tolerable for most patients.

Charles Ryan, MD, from the University of California, San Francisco, and lead investigator of the COU-AA-302 study, stressed that the addition of prednisone to AA therapy has a triple purpose. &ldquo;First, steroids have been traditionally used as a palliative treatment to control bone pain from the disease. Prednisone has always been included in the packets of treatments that included chemotherapy. That formed the basis for the FDA saying that prednisone is an acceptable treatment for some CRPC,&rdquo; Ryan said. &ldquo;Second, patients respond to steroids. The number of patients who have shown a clinical response to steroids alone is somewhere between 20% and 30%. So steroids have therapeutic efficacy as well as palliative benefits. Third, prednisone reduces the mineralocorticoid excess that can occur from abiraterone monotherapy. As such, AA is made safer with the addition of prednisone.&rdquo;

Early phase I and II trials of AA demonstrated antitumor activity, and common AEs, such as hypokalemia, fluid retention, and hypertension associated with mineralocorticoid excess, were significantly reduced with co-treatement with low-dose corticosteroids, such as prednisone.

Given those initial positive results, additional phase III trials were completed using the AA-prednisone combination to determine its efficacy and safety in patients with CRPC.

In the phase III COU-AA-301 trial, patients with mCRPC who had received prior chemotherapy with docetaxel were treated with prednisone 5 mg twice daily plus AA 1000 mg or placebo to determine the effect on OS, time to prostatespecific antigen (PSA) progression (TTPP), and progressionfree survival (PFS). The initial results of the study were reported by Johann de Bono, MD, PhD, from the Institute of Cancer Research in London, and colleagues in The New England Journal of Medicine,

and the final analysis was reported by Fizazi and colleagues in The Lancet Oncology.

Based on the final analysis of 1195 patients, all outcomes favored the AA treatment group. Compared with placebo, AA plus prednisone extended median OS (15.8 vs 11.2 months; P <.0001), median radiologic PFS (5.6 vs 3.6 months; P <.0001), median TTPP (8.5 vs 6.6 months; P <.0001), and proportion of patients with a PSA response (29.5% vs 5.5%; P <.0001).10 Mineralocorticoid-related AEs were more common in the AA-plus-prednisone group than with placebo plus prednisone, although grade 3/4 AEs were similar between treatment groups.

The phase III COU-AA-302 examined the safety and efficacy of AA plus prednisone in 1088 patients with mCRPC without prior chemotherapy. Patients were treated in a similar fashion as in the COU-AA-301 study. The primary outcomes were radiologic PFS and OS. Interim results were reported by Dana Rathkopf, MD, from Memorial Sloan Kettering Cancer Center in New York City, and colleagues in European Urology,11 and the final analysis reported by Charles Ryan, MD, from the UCSF Helen Diller Family Comprehensive Cancer Center, and colleagues in The Lancet Oncology.

Analysis of Varying Dosing of Glucocorticoids

After an extended follow-up period, patients who had received AA plus prednisone had significantly longer median OS (34.7 vs 30.3 months; P =.0033) and PFS (16.5 vs 8.2 months; P <.0001) than with placebo.

Similar to the COUAA-301 trial, AEs related to mineralocorticoid excess were more common with AA than with placebo, although most were grade 1 or 2 in severity.

Ongoing clinical trials are evaluating various dosing and glucocorticoid combinations with AA in patients with mCRPC to determine the incidence of AEs associated with mineralocorticoid excess. Gerhardt Attard, MD, PhD, from the Institute of Cancer Research in London, and colleagues presented their findings at the 2016 Genitourinary Cancers Symposium.

In the phase II trial, 164 patients with asymptomatic chemotherapy-naive mCRPC were randomized to receive AA 1000 mg once daily plus prednisone at 1 of 3 different dosing schedules or dexamethasone at 1 dosing schedule. The primary endpoint was the percentage of patients who experienced hypokalemia or hypertension during the first 24 weeks of treatment. In comparison with patients who received prednisone 5 mg once daily or 2.5 mg twice daily, patients who received prednisone 5 mg twice daily and dexamethasone 0.5 mg once daily had lower rates of overall hypokalemia (14.6% and 7.7% vs 7.3% and 9.5%, respectively) and hypertension (36.6% and 30.8% vs 14.6% and 11.9%, respectively). A similar trend was observed for grade 3 AEs, and there were no grade 4 events (

These data indicate that the approved dosing of prednisone 5 mg twice daily with AA or dexamethasone 0.5 mg once daily can adequately prevent mineralocorticoid excess‒associated AEs. However, additional research will be needed before there is acceptance of a lower prednisone strategy.

In summary, the long-term use of prednisone with AA appears to be safe and well tolerated in patients with mCRPC. Additionally, the use of prednisone offers multidimensional benefits. &ldquo;Many patients with advanced prostate cancer have a pain component to their disease,&rdquo; Ryan stated. &ldquo;We need to remember that prednisone can help to manage some of the pain issues. It does continue to provide a palliative benefit, and it probably contributes to the clinical benefit of abiraterone overall.&rdquo;

Crawford ED. Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology. 2009;73(5 suppl):S4-10.

Halabi S, Small EJ, Kantoff PW, et al. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol. 2003;21(7):1232- 1237.

Massard C, Fizazi K. Targeting continued androgen receptor signaling in prostate cancer. Clin Cancer Res. 2011;17(12):3876-3883.

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.

Fizazi K, Chi KN, de Bono JS, et al. Low incidence of corticosteroid-associated ad- verse events on long-term exposure to low-dose prednisone given with abiraterone acetate to patients with metastatic castration-resistant prostate cancer [published online March 7, 2016]. Eur Urol. doi: 10.1016/j.eururo.2016.02.035.

Danila DC, Morris MJ, Bono JS de, et al. Phase II multicenter study of abiraterone ac- etate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010;28(9):1496-1501.

Reid AHM, Attard G, Danila DC, et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28(9):1489-1495.

Attard G, Reid AHM, A&rsquo;Hern R, et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009;27(23):3742-3748.

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.

Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU- AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13(10):983-992.

Rathkopf DE, Smith MR, de Bono JS, et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol. 2014;66(5):815-825.

Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus pla- cebo plus prednisone in chemotherapy-naive men with metastatic castration-resis- tant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.

Attard G, Merseburger AS, Sternberg CN, et al. A randomized trial of abiraterone acetate (AA) administered with 1 of 4 glucocorticoid (GC) regimens in metastatic castration-resistant prostate cancer (mCRPC) patients (pts). J Clin Oncol. 2016;34(2_ suppl; abstr 261).

Articles

Clinical Articles

For decades, the standard of care for men with advanced prostate cancer has been the depletion or inhibition of androgens. While androgen-deprivation therapy (ADT) often results in temporary tumor regression or symptom relief in some patients, disease progression ultimately occurs over time.

Steroid Use With Abiraterone Offers Multidimensional Benefits to Patients With mCRPC

It is most frequently diagnosed in men age 65 to 74 years, with nearly 90% of all new cases diagnosed in men age &ge;55 years.

Given the demographic distribution of patients with prostate cancer, clinicians must consider and evaluate the unique characteristics and treatment options for this population. Unlike younger men, older men are more likely to be diagnosed with advanced disease, and tend to have higher mortality rates and poorer prognosis.

Many older patients with prostate cancer are treated with systemic therapies, stressing the importance of evaluating clinical outcomes and safety profiles specifically in the elderly. Treating elderly patients presents certain challenges, including higher rates of comorbidities, physical frailty, and lower tolerance for adverse events (AEs). Several recent studies have investigated the safety and efficacy of next-generation antiandrogen therapies and chemotherapy in the geriatric population.

Peter Mulders, MD, PhD, Radboud University Medical Center, Nijmegen, The Netherlands, and colleagues reported their findings of abiraterone acetate in elderly patients who had received prior chemotherapy in European Urology.

In a post hoc analysis of the COU-AA-301 trial,5,6 the pivotal study that led to the approval of abiraterone acetate in patients who had received prior docetaxel, the efficacy and safety of abiraterone acetate (AA) plus prednisone was compared with placebo plus prednisone in younger (<75 years) and elderly (&ge;75 years) patients.

Abiraterone acetate, the prodrug of abiraterone, is an inhibitor of CYP17A that targets extragonadal synthesis of androgen. Since 2011, it has been approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) who have received prior docetaxel therapy, and since 2012 for patients who are chemotherapy-naïve (

Compared with patients who received placebo plus prednisone, overall survival (OS) was significantly improved with AA plus prednisone in elderly patients (15.6 vs 9.3 months; P =.0022) and younger patients (15.9 vs 12.0 months; P =.0055). Similarly, AA plus prednisone significantly improved radiographic progression-free survival (PFS) in both elderly (6.6 vs 5.4 months; P =.0019) and younger (5.6 vs 3.0 months; P <.0001) patients, as well as time to prostate-specific antigen (PSA) progression (TTPP) in younger patients (8.4 vs 5.6 months; P <.0001).

Grade 3/4 AEs were similar in both age groups. Rates of hypertension and hypokalemia, both associated with AA and mineralocorticoid excess, were greater in the AA-plusprednisone cohort, although rates were similar between age groups. Treatment-related cardiac events that led to study discontinuation were also similar between both treatment and age groups (1% vs 1%).

&ldquo;This analysis is reassuring with respect to the riskbenefit ratio of treating elderly patients with AA, and AA is a viable treatment option for the elderly, either after docetaxel or for those not fit for docetaxel due to other comorbidities,&rdquo; the authors concluded.

Outcomes were further explored in an elderly population, in parallel post hoc analyses of the COU-AA-302 trial, which was the landmark study that led to the approval of AA in chemotherapy-naïve patients.

Further results were also published in the November 2015 issue of The Journal of Urology (

Clinical outcomes were significantly improved with AA plus prednisone compared with prednisone alone. For AA plus prednisone, radiographic PFS was superior in both elderly (14.9 vs 8.3 months; P =.0009) and younger (16.6 vs 8.3 months; P <.0001) cohorts, as well as OS in elderly patients (28.6 vs 25.6 months; P =.0268). All secondary endpoints also favored AA plus prednisone for both age groups. Adverse events associated with AA plus prednisone were similar between age groups.

Mineralocorticoid excess events (edema, hypokalemia, hypertension) occurred more frequently with AA plus prednisone than with prednisone alone in both elderly and younger patients. Although infrequent, grade 3 or 4 hepatoxicity and cardiac disorders were more frequent in both age cohorts with AA plus prednisone.

In conjunction with the results reported by Mulders et al, these findings &ldquo;support the use of abiraterone therapy in elderly men with mCRPC regardless of prior chemotherapy,&rdquo; Smith and coauthors wrote.

Comparable results have been observed in other studies. In one retrospective trial, Raya Leibowitz-Amit, MD, PhD, from Tel Aviv Hospital in Israel, and colleagues evaluated the toxicity and efficacy of AA and docetaxel in patients with mCRPC age &ge;80 years, assessing PSA response rate, incidence of toxic AEs, OS, and biochemical PFS.

Relative to younger men, octogenarians had similar rates of PSA response rate, biochemical PFS, and OS with AA therapy. Treatment was well tolerated in both age groups, with no significant differences in mineralocorticoid excess events and mild liver toxicity rates.

The investigators stressed that despite this analysis being retrospective in nature, it reflects a &ldquo;real life&rdquo; experience because most data were obtained outside of a clinical trial. Taken together, the results of these studies support the use of AA in an elderly population, especially for patients who may be more sensitive to alternative therapies with greater toxicity.

In the February 2014 issue of Annals of Oncology, Cora Sternberg, MD, from San Camillo-Forlanini Hospital in Rome, Italy, and coauthors reported the outcomes of younger and elderly patients treated with enzalutamide who had received prior docetaxel therapy using a post hoc analysis of the AFFIRM trial (

). Efficacy outcomes for OS, radiographic PFS, TTPP, and PSA response, as well as safety, were assessed.

Enzalutamide is an androgen receptor inhibitor that competitively binds to its ligand-binding domain. It has been approved for use in patients with mCRPC both before and after docetaxel.

In both age cohorts, OS was significantly longer with enzalutamide compared with placebo (younger: median not reached vs 13.6 months; P <.0001; elderly: 18.2 vs 13.3 months; P = .004). Similarly, radiographic PFS was improved in younger (HR, 0.45; P <.001) and elderly (HR, 0.27; P <.001) patients with enzalutamide, as was TTPP and PSA response. The incidence of all-grade peripheral edema, fatigue, and diarrhea were greater in elderly patients than in younger patients with enzalutamide. Grade &ge;3 AEs were similar between both age groups and treatment cohorts.

In a more recent report in the February 2016 issue of Annals of Oncology,

Julie Graff, MD, from Oregon Health and Science University, and co-investigators analyzed the safety and efficacy of enzalutamide in younger and older patients with mCRPC who were chemotherapy-naïve using a post hoc analysis of the PREVAIL clinical trial (

Among elderly patients, OS and radiographic PFS were significantly improved with enzalutamide compared with placebo. The incidence of AEs was similar between age groups and treatment groups, with the exception of falls, which was greater in elderly patients compared with younger patients, and in elderly patients treated with enzalutamide compared with placebo.

Investigators reasoned that the data from this study as well as previous post hoc analyses support that &ldquo;secondgeneration hormone therapy is safe and effective in men aged &ge;75 years, reinforcing the stance that physicians should not discriminate on the basis of age alone when selecting treatment for mCRPC.&rdquo;

Enzalutamide does not require concomitant corticosteroid treatment. In terms of sequencing, the authors pointed out that AA and enzalutamide have unique safety profiles that should be carefully evaluated when making therapy selection for elderly patients.

Until recent years, docetaxel was the only chemotherapeutic agent available that offered a survival advantage in mCRPC. Compared with mitoxantrone, docetaxel significantly improved OS and quality of life. However, toxicity in elderly patients, namely myelosuppression and sepsis, has been of concern. In the TAX327 trial, elderly patients age &ge;75 years experienced significantly higher rates of infection and needed more docetaxel dose reductions than younger patients.

To address these toxicity concerns, Hui-Li Wong, MD, from the Walter & Eliza Hall Institute of Medical Research in Sydney, Australia, and colleagues evaluated dosing practices, efficacy, and tolerability in very elderly patients (age &ge; 80 years) in a retrospective study of 20 patients with mCRPC.18 Although 56% of assessable patients had a PSA response rate of &ge;50%, 40% required an initial dose reduction, and 55% required subsequent dose delays or reductions. Grade 3/4 hematologic toxicity occurred in 45% of patients, and chemotherapy-related complications requiring hospitalization occurred in 25% of patients.

Similarly, in the analysis by Leibowitz-Amit et al,

PSA response rates and OS were similar in octogenarians and younger men, although toxicity-related docetaxel cessation and febrile neutropenia occurred more frequently in octogenarians.

&ldquo;Our results suggest that amelioration or prevention of chemotherapy-induced-toxicity is difficult in octogenarians even with modification of dose and schedule [with docetaxel], and that even awareness and careful vigilance of treating physicians cannot mitigate toxicity altogether,&rdquo; Leibowitz-Amit and coauthors concluded.

Overall, advances in recent years have broadened the therapeutic options for all patients with mCRPC. In order to provide optimal clinical outcomes for elderly patients, clinicians must carefully weigh the individual needs of the patient against the safety and efficacy of specific agents, while remembering that elderly patients may have different goals of care than younger populations.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30.

National Cancer Institute. SEER Stat Fact Sheets: Prostate Cancer. 2016. http:// seer.cancer.gov/statfacts/html/prost.html. Accessed April 5, 2016.

Scosyrev E, Messing EM, Mohile S, et al. Prostate cancer in the elderly: frequency of advanced disease at presentation and disease-specific mortality. Cancer. 2012;118(12):3062-3070.

Mulders PFA, Molina A, Marberger M, et al. Efficacy and safety of abiraterone acetate in an elderly patient subgroup (aged 75 and older) with metastatic castration-resistant prostate cancer after docetaxel-based chemotherapy. Eur Urol. 2014;65(5):875-883.

Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13(10):983-992.

Kessler ER, Flaig TW. Geriatric considerations in the treatment of advanced prostate cancer. F1000Prime Rep. 2014;6:33.

Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castrationresistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.

Smith MR, Rathkopf DE, Mulders PFA, et al. Efficacy and safety of abiraterone acetate in elderly (75 years or older) chemotherapy naïve patients with metastatic castration resistant prostate cancer. J Urol. 2015;194(5):1277-1284.

Leibowitz-Amit R, Templeton AJ, Alibhai SM, et al. Efficacy and toxicity of abiraterone and docetaxel in octogenarians with metastatic castration-resistant prostate cancer. J Geriatr Oncol. 2015;6(1):23-28.

Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197.

Sternberg CN, de Bono JS, Chi KN, et al. Improved outcomes in elderly patients with metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: results from the phase III AFFIRM trial. Ann Oncol. 2014;25(2):429-434.

Graff JN, Baciarello G, Armstrong AJ, et al. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. Ann Oncol. 2016;27(2):286-294.

Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424-433.

Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513-1520.

Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.

Wong HL, Lok SW, Wong S, et al. Docetaxel in very elderly men with metastatic castration-resistant prostate cancer. Prostate Int. 2015;3(2):42-46.

Several recent studies have investigated the safety and efficacy of next-generation antiandrogen therapies and chemotherapy in the geriatric population.

Challenges in the Optimal Therapeutic Management of Geriatric Patients

To gain insight into current best practices and strategies that are on the horizon,

spoke with two of the leading experts in the field: E. David Crawford, MD, endowed chair in Urologic Oncology at the University of Colorado, and Leonard G. Gomella, MD, senior director for Clinical Affairs at Jefferson Kimmel Cancer Center.

What factors guide your selection of frontline therapy for men with CRPC?

We are entering an era of castration-resistant prostate cancer where we are trying to really personalize it to the patient, and not just throw out a big net and say, &ldquo;everybody fits into this one.&rdquo; You look at how fast they got there, how they got there, what prior treatments they receivedmany other things like that.

The good thing is, we have a whole bunch of things to treat patients with. In general, they are not for patients who are sort of &ldquo;circling the drain,&rdquo; but for the minimally symptomatic patient.

What I normally would do is think about things I really want to get into the patientthings like immunotherapy or sipuleucel-T. I sort of consider that a platform you really build on. The question is, &ldquo;Do you start with an androgen biosynthesis inhibitor? Do you start out with radium-223? Do you start out with things like anti-androgens, such as enzalutamide? Do you put combinations together?&rdquo; Those are all conversations you need to have with the patient.

Right now, people are doing things like sequencing. I think we need to start thinking beyond that. We need to think about the fact that, in most cancers that we cure, it&rsquo;s not sequencing &ldquo;A, B, C, and D,&rdquo; it&rsquo;s putting &ldquo;A, B, C, D&rdquo; together and treating the patient. It may not be for a lifetime; it may be a short time.

That is certainly the case for certain lymphomas, leukemias, and testicular cancers, and I think the same thing really applies to prostate cancer.

Currently, I think people tend to start out with the bettertolerated agents and then move to the drugs that have more significant side effects. That means that chemotherapy has been pushed to the end of the line again. But, in newly diagnosed patients, that&rsquo;s different.

When we look at managing patients with castration-resistant prostate cancer, we have many options available to us right now. We are learning, as time goes on, that certain agents are best used early in the course of the disease; meanwhile, other agents may be used early but may be optimally used later. A classic example of that is using sipuleucel-T very early in the course of CRPC, when patients are minimally symptomatic or asymptomatic. It is probably not a good idea to use it later when people have a lot of pain or other symptoms.

In general, we like to use agents such as immunotherapy with sipuleucel-T early in the disease. Other agents are certainly valid to use. The androgen receptor-pathway blockers enzalutamide and abiraterone are certainly fair to use early in the course of the disease. More recently, for patients with metastatic castration-resistant prostate cancer, there tends to be use of chemotherapy a little bit later in the course of the disease. However, that is variable depending on local practice patterns and how the medical oncologists really feel about the use of chemotherapy.

Radium-223 is out there, also. The difference with radium-233 is it can be used across the spectrum of the disease, but it tends not to be used early in current practice. It tends to be used a little bit later. However, using it early is something that is under investigation, as well.

Which do you use first and why: abiraterone acetate or enzalutamide?

How do you sequence abiraterone and enzalutamide? Again, a lot of things influence that decision. Has the patient been on anti-androgen therapies before? Had he received ketoconazole? Did he receive this or that? It is a lot of things.

In general, I use both. I sort of look at the studies out there and offer patients the opportunity to get abiraterone, and I discuss the risks and benefits associated with that. It&rsquo;s the same with enzalutamide. It&rsquo;s not an easy question to answer. The question goes really beyond that, tooputting things together. Does it make sense to put them both together? I don&rsquo;t know. We need to look at that.

In general, the agents are both very effective for metastatic castration-resistant prostate cancer. They are both oral agents, and they are fairly easily used in the outpatient setting.

There are some general rules of the road that we follow in our multidisciplinary clinic when we treat men with these agents. For example, if someone has a history of seizure disorders and head trauma, or anything related to the central nervous system, we tend to avoid enzalutamide. If someone has very brittle diabetes or significant problems with the management of their diabetes, we tend to avoid abiraterone. But, to be fair, both of them are very good agents in the frontline setting.

How has your real world experience with these agents differed from the clinical trial results?

Clinical trials are very narrow. Most of them start out at post-chemotherapy or pre-chemotherapy, and now it is even in patients who are newly diagnosed, metastatic, or have rising PSA. Even enzalutamide is being used in active surveillance programs. The great thing is that you now have these tools, and they&rsquo;re different. People who go on clinical trials are a very select group of men, in a way.

Now, we have a broader brush we can use to treat them. We&rsquo;ll use enzalutamide earlier in the disease, or we&rsquo;ll use abiraterone or radium-223 earlier in the disease. Radium-223 started out as a drug that patients sort of received post-chemotherapy. Half of the people on the clinical trial ended up receiving pre-chemotherapy. Now we know, because of that, it is better to receive it pre-chemotherapy. It&rsquo;s not for people who are sort of &ldquo;circling the drain&rdquo; with the disease.

In general, what we whave learned is that the clinical trials are fairly representative of what we see. The side effect profiles that sometimes get reported in the clinical trial may not be as important as we see in the real world setting. A good example is a lot of people are afraid, or a lot of providers may be afraid, of using prednisone along with an agent such as abiraterone.

As the treatment landscape for patients with metastatic castration-resistant prostate cancer (CRPC) continues to evolve, optimal strategies are becoming more apparent on how to best sequence the multitude of novel therapies that have been approved in the past decade.

Experts Discuss Treatment Sequencing Strategies in CRPC

Medication Adherence With Oral Anti-Cancer Therapies

The number and availability of oral anti-cancer drugs has increased in recent years. While multiple studies have indicated that the majority of patients prefer oral therapy compared with intravenous therapy, this also shifts a large part of medication adherence responsibility from the clinician to the patient. The linkage between adherence rates and treatment efficacy may have a significant impact on patient outcomes; as such, medication adherence represents an increasing concern for the optimal therapeutic management of patients with mCRPC. Historically, determining adherence to anti-cancer therapies has been difficult to predict, with rates varying widely between 16% and 100%.

In January 2016, Ajay Behl, PhD, and colleagues presented data on the treatment gaps in patients with mCRPC who were treated with abiraterone or enzalutamide at the 2016 Genitourinary Cancers Symposium.

Abiraterone acetate, an inhibitor CYP17A1 that blocks extragonadal androgen biosynthesis, and enzalutamide, a direct antagonist of the androgen receptor (AR), are among the nextgeneration agents most recently approved for use in mCRPC. Both agents are available as oral therapies.

In the retrospective study, investigators utilized the Truven Health MarketScan Research Databases to analyze nearly 3400 patients with mCRPC who were initiated on either abiraterone or enzalutamide therapy. Patient discontinuation patterns were observed until loss to follow-up or data unavailability, and Kaplan-Meier survival curves compared the rates of having a refill gap (

Compared with patients initiating with abiraterone therapy, patients initiating with enzalutamide had significantly higher rates of refill gaps of &ge;30 days or &ge;60 days after 6 months (&ge;30 days: 18.3% vs 11.7%; &ge;60 days: 8.4% vs 5.2%), 9 months (&ge;30 days: 24.9% vs 16.9%; &ge;60 days: 12.7% vs 7.9%), and 12 months (&ge;30 days: 30.1% vs 20.9%; &ge;60 days: 15.9% vs 9.1%).

Little additional data are available on the specific adherence rates of abiraterone or enzalutamide. In one US study of patients taking abiraterone acetate plus prednisone, the adherence rate, as measured by the medical possession ratio (MPR), was >90% after 6 months, 9 months, and 12 months.

A Canadian study found that optimal adherence, as defined by an MPR of at least 80% at 6 months, was achieved by 83% of patients. Nearly 80% achieved an MPR of &ge;90%. At 1 year, 82% of patients maintained optimal adherence.

While these data support that nonadherence to abiraterone is relatively low, additional studies are needed to determine the reasons driving nonadherence with enzalutamide and potential contributing factors. To date, no other specific data exist that have examined the adherence rate of patients receiving enzalutamide. The reasons for oral anti-cancer therapy nonadherence are complex and involve several factors. A systematic review by Verbrugghe et al

examined 25 studies to identify some of the associated factors related to nonadherence and nonpersistence with oral anti-cancer therapy. Nonadherence factors included patient-related factors (lower perceived necessity, perception of no benefit with adherence, lower perceived quality of life and concerns about symptoms), therapy-related factors (treatment-related AEs, longer duration of therapy, greater number of prescriptions), disease-related factors (comorbidities), healthcare system factors (duration of followup visits, different providers during follow-up, less patient participation in decision making), and social and economic factors (age, out-of-pocket costs).

Examination of Adverse Events Associated with Enzalutamide in a Real-World Setting

Comparisons of the safety and efficacy of first-generation antiandrogens, such as bicalutamide, against the next-generation therapies, such as enzalutamide, in mCRPC are ongoing. Because bicalutamide and enzalutamide function to suppress AR signaling through different mechanisms, and bicalutamide has the potential to act as an AR agonist, it is necessary to investigate its clinical utility in the setting of mCRPC. However, both clinical safety and efficacy must be addressed when selecting a therapeutic regimen.

In the recently published, pivotal phase II study, TERRAIN, Neal Shore, MD, Carolina Urologic Research Center in Myrtle Beach, SC, and colleagues reported on the clinical efficacy and safety of enzalutamide versus bicalutamide in patients with mCRPC.6 Compared with bicalutamide, treatment with enzalutamide significantly increased progression-free survival (HR, 0.44; 95% CI, 0.34-0.57; P <.0001). Serious AEs were reported in 31% of patients treated with enzalutamide and 23% of patients treated with bicalutamide. Grade 1 or 2 AEs that were more common with enzalutamide included fatigue, hot flush, and extremity pain. Two patients who received enzalutamide and 1 who received bicalutamide experienced a seizure.

Although the TERRAIN trial provided pivotal safety data, the rates of central nervous system (CNS) and seizure events in a nonclinical trial population were unknown. Behl et al

presented a retrospective study comparing the rates of real-world CNS events in patients treated with enzalutamide or bicalutamide at the 2016 Genitourinary Cancers Symposium.

Patient data were again obtained using the Truven Health MarketScan Research Databases. Exclusion criteria included any other CNS conditions or cancer diagnoses during the baseline period. Analyzed CNS conditions included amnesia, anxiety, ataxia, cognitive disorders, dizziness, falls, fatigue, headaches, insomnia, pain, paresthesia, seizures, and weakness. The rates of CNS events were compared between treatment groups using Kaplan-Meier survival curves.

For all patients, CNS events occurred at a significantly greater frequency (P <.0001) in patients initiating enzalutamide as compared with bicalutamide at all time points measured (3-18 months). Similarly, when controlling for metastatic status, patients in the enzalutamide cohort had significantly greater (P <.05) CNS events than patients in the bicalutamide cohort after 9 to 18 months of treatment.

Behl stated, &ldquo;It is important to examine the rate of CNS events in a non-clinical trial setting because the patient population in the real world may be different than in clinical trials. The standards of care in the real world do not require that patients be monitored as frequently as is generally practiced in clinical trials. This can have a complex effect on the kind of adverse events that are observed and recorded by providers in the real world setting.&rdquo;

Although the data are limited, enzalutamide treatment has been associated with a greater incidence of falls in elderly patients (&ge;75 years) than in younger patients (<75 years) when compared with placebo.8 In a report by Foster and colleagues,

an in vivo, nonclinical analysis examined the pharmacologic safety of several AR antagonists specifically related to CNS events and any off-target effects. Compared with bicalutamide, enzalutamide was associated with a greater number of convulsions, lower IC50 for gamma-aminobutyric acid (GABA)-A, and higher brain drug concentration associated with convulsion. The GABAA channel is an established mediator of seizure; the ability of AR antagonists to inhibit GABA-A may be one explanation for the CNS events and seizures that have been reported both in clinical and nonclinical studies.

&ldquo;The possibility that AR antagonists cause seizure through GABA-A inhibition creates some useful hypotheses relative to the drug safety and side effect profiles of existing and new AR antagonist therapies,&rdquo; the authors wrote. They added, &ldquo;Some theoretical negative side effects of GABA-A antagonism could be significantly masked by the beneficial effects of AR antagonist drugs.&rdquo;

In a similar observational study by Behl et al,10 the development of CNS events was analyzed in nearly 1067 patients with mCRPC initiated on abiraterone acetate, enzalutamide, or chemotherapy using a large nationwide healthcare claims database. CNS events were significantly less likely to occur in patients who received abiraterone acetate compared with enzalutamide (39.5% vs 46.0%; P =.0036) or chemotherapy (39.5% vs 51.1%; P =.0277) after 12 months. Using a multivariate adjustment, patients in the abiraterone acetate cohort also had a significant reduction in the hazard of having a CNS event compared with the other treatment cohorts (20% vs enzalutamide; P = .0388).

At least 1 additional prospective phase II study will address potential cognitive effects of abiraterone and enzalutamide in patients with mCRPC.

Since 2010, several novel therapies have been approved for use in metastatic castration-resistant prostate cancer (mCRPC). Although they have expanded the therapeutic repertoire for clinicians, they also bring a new set of challenges for the optimal clinical management of patients with mCRPC.

Analysis of Real-World Data for Next-Generation Antiandrogen Therapies

Within the past 5 years, several agents have become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on survival benefits observed in randomized clinical trials. The FDA approved abiraterone acetate (Zytiga; the prodrug of abiraterone and inhibitor of CYP17A1 that blocks extragonadal, testicular, and intratumoral androgen synthesis) and enzalutamide (Xtandi; a direct inhibitor of the androgen receptor that attenuates its activation and signaling within the nucleus) in 2011 and 2012, respectively, for the treatment of mCRPC. Although each has demonstrated improved survival outcomes, the optimal sequencing of these therapies has not been established, and most patients exhibit some degree of cross-resistance.

Examining the Optimal Sequencing of Therapies

Benjamin Maughan, MD, from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD, and colleagues presented their findings on the optimal sequencing of abiraterone and enzalutamide in men with mCRPC at the Genitourinary Cancers Symposium in January 2016.

In the retrospective study of 71 patients, 58 received abiraterone followed immediately by enzalutamide (abi-to-enza) and 13 received enzalutamide followed immediately by abiraterone (enza-to-abi). The primary endpoint was combined progression-free survival (PFS), measured from initiation of the first therapy until disease progression on the second therapy. The secondary endpoint was overall survival (OS), from the start of the first therapy until death (

Compared with the enza-to-abi group, the abi-to-enza group had significantly longer combined PFS (16.3 vs 12.5 months; HR, 0.53; P =.04). Overall survival was also numerically longer for the abi-to-enza group, although the difference did not reach statistical significance (29.0 vs 21.0 months; HR, 0.51; P <.10). Using multivariable analyses to account for differences in prostate-specific antigen (PSA) levels, hemoglobin, visceral disease, and prior docetaxel use, the abi-to-enza sequence showed improvements in both combined PFS (HR, 2.59; P =.03) and OS (HR, 4.59; P <.01).

The results of this preliminary study suggest that the sequence of abiraterone followed by enzalutamide may produce clinically superior outcomes in men with mCRPC compared with enzalutamide followed by abiraterone. However, investigators caution that results could be due to baseline imbalances in the study population and the small sample size.

The senior author of the study, Emmanuel S. Antonarakis, MD, also with the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, noted, &ldquo;The evidence that abiraterone is superior to enzalutamide in terms of optimal sequencing is very weak right now, and these data should only be viewed as hypothesis-generating. That question can only be conclusively answered by prospective studies.&rdquo;

To address this point, an ongoing, prospective phase II clinical trial is under way (NCT02125357). Investigators will randomize patients with mCRPC to receive either firstline abiraterone or enzalutamide, and patients will subsequently cross over to the alternative agent at the time of PSA progression. The primary endpoint will be the PSA response rate to the second-line therapy in each arm. Since androgen receptor (AR) activation drives PSA expression, PSA response will be used to determine abiraterone and enzalutamide efficacy. Secondary outcome measures will assess potential circulating biomarkers that are associated with treatment efficacy and resistance, including AR mutations as well as AR splice variants (

Additional studies have examined the clinical efficacy of sequential therapy and have shown modest results. In a study by Schrader et al,

35 patients who had received prior docetaxel chemotherapy were treated sequentially with abiraterone followed by enzalutamide. After abiraterone treatment, 46% of patients achieved a >50% decline in PSA. Among those who were abiraterone-sensitive, 44% achieved a >50% PSA decline with enzalutamide treatment; among those who were abiraterone-insensitive, only 16% achieved a >50% PSA decline with subsequent enzalutamide.

Using data from the phase III AFFIRM clinical trial, Noonan and colleagues5 retrospectively analyzed PSA response in 30% of patients with mCRPC who had progressed with enzalutamide and were subsequently treated with abiraterone. After enzalutamide treatment (median duration, 41 weeks), 70% had a &ge;30% PSA decline. However, after abiraterone treatment (median duration, 13 weeks), only 3 patients had a &ge;30% PSA decline, no patients demonstrated a radiographic response, and the median time to progression was 15 weeks.

Taken together, these studies collectively suggest that sequential therapy with either abiraterone followed by enzalutamide or vice versa is somewhat limited by the potential for cross-resistance between therapies. Although many patients will experience significant clinical benefit from abiraterone and enzalutamide given alone or in combination, 20% to 40% of patients are resistant to each therapy. Among those who respond initially, nearly all will acquire secondary resistance.

Identifying biomarkers and examining molecular mechanisms that may be responsible for the cross-resistance between these agents is critical for determining optimal treatment sequencing and which patients are most likely to respond to a given therapy. Current therapeutic decision making requires a more nuanced approach that takes into consideration a number of patient and physician factors.

Potential Mechanisms of Resistance to Androgen Receptor‒Targeted Therapies

Several groups are examining the mechanisms of resistance to abiraterone, enzalutamide, and other next-generation ARtargeted therapies for mCRPC. According to Antonarakis, the identification of biomarkers associated with resistance requires an integrated analysis of 3 critical components of AR biology: (1) amplification or overexpression of the AR gene; (2) activating DNA mutations in the AR ligand-binding domain; and (3) AR mRNA splice variants (TABLE 2).

Androgen receptor gene amplification and overexpression are commonly observed in patients with prostate cancer in response to androgen-deprivation therapy and novel AR-targeted therapy. Ongoing studies are evaluating the extent of AR amplification and its influence on resistance to novel antiandrogen therapies. In a recent study, Arun Azad, MD, PhD, with the Vancouver Prostate Cancer Centre, in Canada, and colleagues reported on the prevalence of AR gene aberrations and their association with therapeutic resistance in CRPC in Clinical Cancer Research.

Androgen receptor gain or amplification was identified in 28 of 62 (45%) patients. Compared with patients who had progressed on abiraterone or other agents, patients who progressed on enzalutamide had significantly higher frequency of AR amplification (53% with enzalutamide versus 17% and 21% with other agents and abiraterone, respectively; P =.02). Androgen receptor amplification was associated with inferior outcomes to both abiraterone and enzalutamide.

Several activating mutations in the AR ligand-binding domain have also been identified. Such mutations can result in promiscuous activation by other adrenal androgens, steroidal and nonsteroidal ligands, and conversion of AR antagonists into agonists. For example, Azad et al

identified the F877L mutation in an enzalutamide-resistant patient, and the H875Y and T878A mutations in 7 abiraterone-resistant patients. The F877L mutation, which alters the conformation of the AR ligand-binding domain, has been associated with enzalutamide resistance because of its ability to drive an antagonist-to-agonist switch.

Antonarakis and colleagues11 have examined the expression of a particular AR splice variant, AR-V7, and its associated resistance to enzalutamide and abiraterone. The results of their study were reported in The New England Journal of Medicine.

Both enzalutamide and abiraterone target the ligand-binding domain of AR, either directly or indirectly. The AR-V7 variant lacks the ligand-binding domain but retains constitutive activity as a transcription factor, potentially explaining the resistance observed with these agents.

Among enzalutamide-treated (n = 31) and abirateronetreated (n = 31) patients with mCRPC, AR-V7 was detected in circulating tumor cells of 39% and 19% of patients, respectively. Compared with patients who were AR-V7negative, AR-V7&ndash;positive patients had significantly lower PSA response rates, shorter PSA PFS, shorter clinical or radiographic PFS, and shorter OS with enzalutamide or abiraterone treatment.

Antonarakis stressed the importance of examining all 3 mechanisms of resistance associated with AR-targeted therapies. &ldquo;If you only focus on one of the three pieces, you are potentially going to miss two-thirds of the explanation for resistance. To date, there has not been a single group, including our own, that has concurrently analyzed all three of those factors at the same time. That needs to be done. Only once we do that, are we truly going to uncover the majority of the resistance mechanisms to enzalutamide and abiraterone. Those types of biomarker analyses need to be built into all future trials that evaluate AR-targeted therapies or their sequencing.&rdquo;

Furthermore, Antonarakis expressed that the long-term goals of these studies are to identify biomarkers that will help determine the optimal therapy sequencing based on a patient&rsquo;s molecular profile, with particular attention to AR status.

&ldquo;My ultimate vision is that every time a patient shifts from one CRPC therapy to another, they would receive a liquid biopsy from a blood sample, and the androgen/AR axis would be analyzed in real time. The patient would be classified based on their AR status (normal AR vs aberrant AR vs AR-null), and then a decision would be made about the next line of therapy based on their AR biology,&rdquo; Antonarakis stated. &ldquo;That process would be repeated every time the patient progresses on their current therapy. In that way, therapy selection would become an iterative process and would be informed at each juncture by current AR status.&rdquo;

Maughan BL, Suzman DL, Nadal RM, et al. Optimal sequencing of enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2016;34(2_suppl; abstr 308).

ClinicalTrials.gov. Sequencing Abiraterone and Enzalutamide in mCRPC. ClinicalTrials.gov Identifier: NCT02125357.

Maughan BL, Antonarakis ES. Androgen pathway resistance in prostate cancer and therapeutic implications. Expert Opin Pharmacother. 2015;16(10):1521-1537.

Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol. 2014;65(1):30-36.

Noonan KL, North S, Bitting RL, et al. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol. 2013;24(7):1802-1807.

Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148.

Azad AA, Volik SV, Wyatt AW, et al. Androgen receptor gene aberrations in circulating cell-free DNA: biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res. 2015;21(10):2315-2324.

Joseph JD, Lu N, Qian J, et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013;3(9):1020-1029.

Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028-1038.

Within the past 5 years, several agents have become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on survival benefits observed in randomized clinical trials

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