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An analysis of the Surveillance, Epidemiology, and End Results (SEER) database reveals that men with advanced prostate cancer treated with abiraterone acetate (Zytiga, Janssen) for 6 months have a significantly higher mortality if they had preexisting cardiovascular disease (CVD).

The finding was highlighted at a media preview ahead of the American Association for Cancer Research (AACR) annual meeting, set for March 29-April 3 in Atlanta, Georgia.

“This is the largest population-based study to examine treatment outcomes of patients with existing CVD,” said presenter Grace Lu-Yao, PhD, associate director for Population Science at the Sidney Kimmel Cancer Center at Jefferson in Philadelphia.

Dr Grace Lu-Yao

“As we move abiraterone acetate treatment to patients with earlier stages of the disease and longer life expectancy, it is important to evaluate whether the benefits outweigh the risks based on the health status of the patients and to ensure that patients are carefully monitored for potential side effects,” Lu-Yao said.

“Given several cross-sectional and post-randomization level 2 evidence studies suggesting an association between luteinizing hormone-releasing hormone (LHRH) agonists such as leuprolide (Lupron, AbbVie) and increased risk of cardiovascular morbidities, these data raise the possibility that abiraterone acetate may also confer such a risk,” prostate cancer expert Anthony D’Amico, MD, PhD, of the Dana-Farber Cancer Institute, Boston, Massachusetts, told Medscape Medical News.  

“However, this is a univariate analysis and does not adjust for potential confounders such as age, comorbidities, medication, tobacco use, and concurrent use of other androgen deprivation therapies [ADT],” he added.

“Given the potential limitations of this study,” D’Amico suggested that definitive evidence for CV risk with abiraterone acetate will be provided from the ongoing RTOG 0815 study. This is a randomized trial in which men were stratified prior to being randomly selected by the Adult Comorbidity Evaluation-27 (ACE-27) index and then randomly assigned to radiation with or without 6 months of ADT for intermediate-risk prostate cancer, with an endpoint of overall survival.

ACE-27 is a validated tool that reflects the number and severity of medical comorbidity, he said.  

“This trial will validate or refute the increased risk of death due to CV disease with ADT use in men with preexisting CV comorbidities,” he said.

Asked to comment for Medscape Medical News, medical oncologist David M. Nanus, MD, chief of hematology and medical oncology at Weill Cornell Medicine and New York- Presbyterian in New York City, who uses abiraterone acetate for his patients, offered additional insights. “This is an interesting, retrospective study that gives us reason to step back and confirm these observations prospectively,” he said.

“Abiraterone acetate is here to stay; we have to learn how to appropriately manage our patients,” he added.

Abiraterone was initially approved in 2011 in combination with prednisone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients who had received prior chemotherapy, and this approval was extended in 2012 to include patients who had no had prior chemotherapy. In addition, abiraterone acetate (in combination with prednisone) was more recently approved in February 2018 for use in high-risk metastatic castration-sensitive prostate cancer.

Retrospective Analysis of SEER

Lu-Yao indicated that the new study was prompted from two observations.

The first was that androgen deprivation therapy (ADT) added to radiation provided long-term survival benefits only for men with minimal or no CVD morbidity; men with moderate or severe CVD morbidities experienced worse survival when ADT was added to radiation therapy (D’Amico et al. JAMA. 2015;314:1291-1293).

The second observation was that although abiraterone acetate is widely used in men with prostate cancer, the outcomes that have been seen in clinical trials may not always be extrapolated into the real-world setting, Lu-Yao suggested.

“Patients with a history of significant cardiovascular disease or uncontrolled hypertension are almost always excluded from clinical trials of abiraterone acetate. However, in the real-world setting, these conditions are very common among men with prostate cancer,” Lu-Yao said.

She pointed out that in the real-world setting, 2 out of 5 men with prostate cancer have uncontrolled hypertension, 2 out of 3 men over the age of 65 years have some cardiovascular disease, 1 out of 3 have a history of congestive heart failure, and 1 out of 5 have a low performance status (ECOG PS >2).

The current study was undertaken to get a better understanding of how real-world men with prostate cancer who are typically excluded from clinical trials respond to treatment with abiraterone acetate, which was approved based on clinical trial data.

Lu-Yao and colleagues obtained population-based data from the SEER database. They identified men who were diagnosed and treated with abiraterone acetate between 2011 and 2014.

The primary endpoint of the study was 6-month overall mortality and changes in hospitalization rates following treatment with abiraterone acetate. Changes in hospitalization risk were measured by incidence rate ratios (IRR) — post-treatment rate divided by pre-treatment rate.

Of the 2845 men who met the study criteria, 1924 (67.6%) had at least one serious CV condition, which included acute myocardial infarction, atrial fibrillation, congestive heart failure, stroke, and ischemic heart disease before starting on abiraterone acetate.

Overall mortality across the CV conditions ranged from 21.4% (for ischemic heart disease) to 25.6% (for myocardial infarction) compared to 15.8% for men with no preexisting CVD.

A Kaplan-Meier graph revealed that most of the survival benefits were seen in the first 6 months for patients with no CVD vs those with CVD.

The increase in hospitalization rate was substantial after the treatment with abiraterone acetate. Men with no preexisting CVD had a 53% increase in hospitalization rate. Among those with preexisting CVD, the increase was between 34% (for atrial fibrillation) and 55% (for acute myocardial infarction).

When used by men with no prior chemotherapy exposure, abiraterone acetate was associated with 34% to 55% increases in hospitalization rate.

“The increased post-treatment hospitalization rate shows that there is risk associated with abiraterone acetate for all patients,” Lu-Yao noted.

“It is very important that patients with advanced prostate cancer understand that the outcomes of abiraterone acetate treatment observed in clinical trials may not apply to patients in the real world, especially those not meeting the eligibility criteria of the clinical trials,” Lu-Yao said.

“Our data show that patients who have preexisting CV disease experienced higher mortality after receiving abiraterone acetate compared with those who do not, and the bulk of the survival differences occurred in the first 6 months,” Lu-Yao summarized.

The data also provide a rationale for relaxing clinical trial exclusion criteria to ensure greater generalizability of trial results to the real world, she said.

Lessons for Clinical Practice

Preview moderator Elizabeth M. Jaffee, MD, AACR president and deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, noted that clinical trials test new therapies in the healthiest of patients. “This has been rationalized as a safety measure by both investigators and sponsors,” she said.

However, as therapies are getting better and patients are living longer, there is a need to start investigating into real-world scenarios more consistently.

Although the study is retrospective, it provides data to support a prospective collection of information. “This is an approved drug so this is like a phase IV-type study where data are collected post-approval,” she noted.

Nanus, from Weill Cornell, noted that this retrospective analysis spanned a time period when abiraterone acetate was approved in patients with mCRPC regardless of prior chemotherapy exposure.

Although approved in 2011 for mCRPC in patients who had received prior chemotherapy, the approval was expanded in 2012 to all patients with mCRPC regardless of prior chemotherapy exposure, he pointed out. “This study had a mixed population of patients, men who were chemotherapy naïve and those who had received prior chemotherapy,” he observed. (Lu-Yao indicated that approximately 20% of the patients studied had prior chemotherapy use.)

“Who manages these patients may also impact outcomes,” Nanus said. Patients who received abiraterone acetate after chemotherapy are typically treated by medical oncologists, while urologists typically prescribe the drug in chemotherapy-naïve patients, he noted.

“In general, urologists may not be aware of the side effects of treatment and may not manage these as stringently as medical oncologists do,” he said. In his own practice, Nanus noted that patients who have preexisting CVD are monitored carefully and frequently. “We watch patients more closely — their cardiac medications, low potassium and electrolyte imbalance, fluid retention, and blood pressure,” he said.

“Abiraterone acetate is not going away. It is given even earlier [in the disease process] now,” Nanus said.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Lu-Yao has no direct conflicts except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.  D’Amico has disclosed no relevant financial relationships. Not related to abiraterone acetate, Nanus reports being on the Data Safety Monitoring Board of Roche/Genentech.

American Association for Cancer Research annual meeting: Abstract 4469. To be presented April 2, 2019.

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