WHAT IS THE best choice of treatment for a man with newly diagnosed metastatic castration-resistant prostate cancer after treatment with androgen-deprivation therapy—abiraterone acetate (Zytiga) plus prednisone, or enzalutamide (Xtandi)? Both drugs achieve similar cancer control in this setting, but they have not been compared head-to-head in a prospective, randomized, controlled trial. This leaves the choice of therapy to a consideration of side-effect profiles, the physician’s experience and comfort level with either or both drugs, and patient factors and preferences.
A number of poster presentations at the 2018 ASCO Annual Meeting sought to compare the two drugs in terms of side effects. Companion studies of longer-term side effects of the respective drugs, based on data from large registration trials, were also presented. Attendees were crowded around these posters, suggesting that more guidance is needed.
“For small groups of patients, it’s obvious that one drug is better than another, but for the typical patient, both are good drugs.”— Matthew R. Smith, MD, PhD
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“The choice between abiraterone acetate plus prednisone or enzalutamide as initial therapy for metastatic castration-resistant prostate cancer is a ‘billion-dollar question.’ The patient should receive one or the other drug. These drugs have never been adequately compared head to head and probably never will be,” said Matthew R. Smith, MD, PhD, Director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center, Boston. “In the registration studies that led to approval, both drugs appeared to provide similar cancer control. The choice comes down to patient factors and differences in side effects. For some patients, one drug is better than the other,” Dr. Smith continued.
Side-Effect Profile
“BOTH ENZALUTAMIDE and abiraterone acetate plus prednisone may lead to worsening fatigue for metastatic castration-resistant prostate cancer patients, and clinical experience has demonstrated varying aspects of cognitive impairment in some patients. Many men with metastatic castration-resistant prostate cancer are already experiencing fatigue and possibly unrecognized cognitive impairment due to their cancer as well as implementation of androgen-deprivation therapy,” said Neal D. Shore, MD, FACS, a urologist at Carolina Urologic Research Center, Myrtle Beach, South Carolina.
“Many of these men who have been on androgen-deprivation therapy for several years have worsening fatigue, sarcopenia, and other androgen-deprivation therapy–associated side effects,” he continued. “Thus, out of the gate, we can expect worsening adverse events when we add another line of castration-resistant prostate cancer therapy targeting the androgen axis. As an observation, prostate cancer patients—especially the elderly—who are more fit at baseline tolerate androgen-deprivation therapy better.”
“The first shot on goal is oftentimes the best shot. The next drug [line of therapy] will usually have a diminished response.”— Neal D. Shore, MD, FACS
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Experts interviewed for this article agreed that abiraterone acetate plus prednisone is not a good choice of initial therapy for men with diabetes, poor glucose control, heart failure, or fluid overload. Abiraterone acetate plus prednisone can lead to hypokalemia and requires monitoring of potassium levels and liver function tests. They also agreed that enzalutamide should not be used in men with seizures, on seizure-lowering medications, or taking medications with epileptogenic potential and fatigue.
“These scenarios represent men at the ends of the spectrum. What about patients in the middle? For these patients, the choice comes down to physician preference,” Dr. Smith said.
“In the absence of head-to-head comparisons, I generally prescribe abiraterone acetate plus prednisone first. My choice rests primarily on longer personal experience with abiraterone acetate plus prednisone in phase I trials and my comfort level. For most patients, abiraterone acetate plus prednisone has somewhat better tolerability. My impression is that more patients discontinue enzalutamide due to side effects,” Dr. Smith said.
Another View
James L. Mohler, MD, FACS
JAMES L. MOHLER, MD, FACS, Associate Director and Senior Vice President for Translational Research and Professor of Oncology at Roswell Park Cancer Institute, Buffalo, New York, and Chair of the National Comprehensive Cancer Network (NCCN®) panel on prostate cancer guidelines has another view.
“Personally, I think enzalutamide has fewer side effects than abiraterone acetate plus prednisone, and the costs and response rates are similar for both drugs. The need for prednisone with abiraterone acetate is a counterbalance to the fatigue and cognitive problems with enzalutamide. The side effects of prednisone are not inconsequential and include suppression of the immune system, increasing the risk of infection. In some countries in Europe, prednisone is not given unless it is needed, which applies to about 25% of patients. If abiraterone acetate could be given without prednisone, it would be a different story,” Dr. Mohler said.
OF NOTE
On July 13, 2018, the U.S. Food and Drug Administration approved enzalutamide (Xtandi) for patients with castration-resistant prostate cancer. This approval broadens the indicated patient population to include patients with either nonmetastatic or metastatic castration-resistant prostate cancer; the drug was previously approved only for the metastatic setting.“This is a good problem to have—two good drugs to choose from. For small groups of patients, it’s obvious that one drug is better than another, but for the typical patient, both are good drugs. There is no compelling evidence [from randomized controlled trials] that sequencing with one is better than another,” Dr. Smith said.
“To use a soccer analogy, there are now a number of good therapeutic selection options. The first shot on goal is oftentimes the best shot. The next drug (line of therapy) will usually have a diminished response,” Dr. Shore said.
Reported Evidence
BOTH DR. MOHLER and Dr. Smith agreed that the poster presentations provide important information and pieces of the puzzle but should not be used to guide treatment. “Posters are not gospel. We need to see the manuscript published in a peer-reviewed journal to have level 1 evidence that tells the whole story,” Dr. Mohler said.
“Posters should not guide treatment unless they are reporting the mature results of a randomized controlled trial. There is little vetting of content for posters. In contrast, publication in a peer-reviewed journal provides compelling evidence,” Dr. Smith said.
Three posters on the topic from ASCO 2018 and one from the 2018 Genitourinary Cancers Symposium are summarized below.
AQUARiUS
EVIDENCE FROM AQUARiUS, a prospective observational multicenter phase IV study, showed that fewer patients with metastatic castration-resistant prostate cancer initiating therapy with abiraterone acetate plus prednisone experience worsening cognitive decline and worsening fatigue compared with enzalutamide over a 6-month period.1 Patients were assessed as to whether they had at least one episode of clinically meaningful worsening of cognitive function and fatigue.
This study enrolled 211 men taking either drug and followed them for 6 months using established instruments to measure patient-reported outcomes for cognition, fatigue, pain, and health-related quality of life. The study will continue for 12 months. Median age was 76 years; 12% had visceral metastases at baseline; and 15% were on opioids at baseline.
REAAcT
THE NONRANDOMIZED multicenter REAAcT study led by Dr. Shore compared both abiraterone acetate plus prednisone and enzalutamide head to head in 100 patients with metastatic castration-resistant prostate cancer.2 About half of the patients were prescribed each drug.
Of note, the trial demonstrated that using the Cogstate instrument (a computerized customizable test battery), approximately 20% of patients had demonstrable cognitive decline at baseline. Age and comorbidities were comparable.
Significantly more patients treated with enzalutamide experienced fatigue on the Functional Assessment of Cancer total score. A trend was observed for more patients experiencing cognitive decline on enzalutamide, but this was not statistically significant.
“This was a prospective, albeit small, study with real-world experience and evidence-based findings. Fortunately, most patients tolerated both drugs very well,” Dr. Shore said.
Retrospective Cohort Study
A RETROSPECTIVE cohort study from the British Columbia Cancer Center, Vancouver, looked at efficacy and tolerability of first-line abiraterone acetate plus prednisone (n = 104) vs enzalutamide (n = 106) for metastatic castration-resistant prostate cancer in men aged 80 years or older.3 This study found that enzalutamide was associated with a superior prostate-specific antigen (PSA) response rate, time to PSA progression, and time to disease progression over a period of 42 months in these men with a median age of about 85 years.
The association remained significant after adjusting for other prognostic factors. Additional clinical factors associated with time to disease progression included the Charlson Comorbidity Index, time to castration resistance, hemoglobin level, and serum alkaline phosphatase level.
More patients treated with enzalutamide required dose reductions for toxicity, mostly for fatigue. Patients who had a dose reduction on enzalutamide had a better median time to disease progression than those without.
Phase II Randomized Trial
THERE IS NO level 1 evidence on the best sequencing of these two drugs. At the ASCO meeting, a poster described a phase II randomized study exploring the sequencing of enzalutamide and abiraterone acetate plus prednisone in 202 patients with metastatic castration-resistant prostate cancer started on either drug.4 For first-line therapy, enzalutamide was superior to abiraterone acetate plus prednisone in terms of PSA response, but no difference in time to disease progression was observed between the two drugs. In general, a trend was observed for an improved response to second-line enzalutamide vs second-line abiraterone acetate plus prednisone.
“The PSA response and time to progression were better for second-line enzalutamide in patients treated with abiraterone acetate plus prednisone than vice versa.”— Daniel Khalaf, MD
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“The PSA response and time to progression were better for second-line enzalutamide in patients treated with abiraterone acetate plus prednisone than vice versa,” said Daniel Khalaf, MD, of the British Columbia Cancer Center. The study also suggested that time to disease progression was worse in prostate cancers with alterations in BRCA2, ATM, and TP53 and improved in those with SPOP mutations.
Unanswered Questions
“THERE ARE many unanswered questions regarding the management of advanced prostate cancer,” Dr. Smith said. “For example, questions remain about the sequencing of abiraterone acetate plus prednisone vs enzalutamide and whether it is better to give abiraterone acetate plus prednisone or enzalutamide vs chemotherapy for newly diagnosed metastatic castration-resistant prostate cancer in men who have been taking androgen-deprivation therapy.”
He continued: “Another question concerns the importance of androgen receptor–targeted therapy for metastatic castration-resistant prostate cancer. If a patient develops metastasis before becoming castration-resistant, should that patient get more intensified chemotherapy? In hormone-sensitive disease, people are debating the use of abiraterone vs docetaxel. And there are maturing studies of enzalutamide in this space.”
Dr. Mohler commented: “No one is exploring the intermittent use of abiraterone acetate plus prednisone or enzalutamide. That would be a good question to study. The costs of these drugs are astronomical. The expense and side effects of these drugs could be mitigated by intermittent administration, but this study probably will not be done.” ■
DISCLOSURE: Drs. Smith, Shore, Mohler, and Khalaf reported no conflicts of interest.
REFERENCES
1. Thiery-Vuillemin A, Poulsen MH, Dourthe L-M, et al: Six-month patient-reported outcome results from AQUARiUS, a prospective, observational, multicenter phase 4 study in patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate + prednisone or enzalutamide. AQUARIUS. 2018 ASCO Annual Meeting. Abstract 5058. Presented June 2, 2018.
2. Shore ND, Saltzstein DR, Sieber PR, et al: Real-world study of enzalutamide and abiraterone acetate (with prednisone) tolerability (REAAcT). Results. 2018 Genitourinary Cancers Symposium. Abstract 296. Presented February 9, 2018.
3. Khalaf DJ, Zou K, Eigl BJ, et al: Efficacy and tolerability of first-line abiraterone + prednisone versus enzalutamide for metastatic castration-resistant prostate cancer in men > 80 years old: A retrospective cohort study. 2018 ASCO Annual Meeting. Abstract 5051. Presented June 2, 2018.
4. Khalaf D, Annala M, Finch D, et al: Phase 2 randomized cross-over trial of abiraterone + prednisone vs enzalutamide for patients with metastatic castration-resistant prostate cancer: Results for 2nd-line therapy. 2018 ASCO Annual Meeting. Abstract 5015. Presented June 2, 2018.
