Abiraterone Effective, Tolerable in Difficult-to-Treat mCRPC Populations

Neal Shore, MD

Abiraterone acetate (Zytiga) in combination with low-dose prednisone showed a low overall incidence of corticosteroid-associated adverse events (AEs) that were not significantly different compared with prednisone alone for patients with metastatic castration-resistant prostate cancer (mCRPC), according to a study published inEuropean Urology.¹

The study, which included 2267 patients from the COU-AA-301 and COU-AA-302 studies, found that the incidence of any grade corticosteroid-associated adverse events (CAAEs) was 25% in the total patient population, 26% in patients receiving abiraterone and prednisone, and 23% for patients who received prednisone alone. Rates for grade III or higher adverse events were 5%, 5%, and 4% for total patient population, patients who received both agents, and the prednisone-alone group respectively.

In addition to an ideal safety profile when used with prednisone, abiraterone has been shown to be well tolerated and efficacious in more challenging patient populations, including those ≥75 years in age. In a study published inThe Journal of Urology,²the safety and efficacy of abiraterone plus prednisone was investigated in elderly (75 or older) chemotherapy-naive patients with mCRPC compared with younger patients.

In the elderly population, radiographic progression-free survival (rPFS) was significantly longer in the abiraterone plus prednisone arm versus the prednisone alone arm. Median rPFS was 14.9 with abiraterone versus 8.3 months with prednisone alone (HR, 0.63; 95% CI, 0.48-0.83,P= .0009). Younger patients on abiraterone plus prednisone also experienced significantly longer rPFS. The median was 16.6 versus 8.3 months with just prednisone (HR, 0.49; 95% CI, 0.40-0.59,P<.0001).

Most patients in both age subgroups tolerated the combination well, with 6% or less receiving dose reductions across the treatment arms. Two elderly and 3 younger patients on abiraterone plus prednisone had dose reductions due to AEs and 1 younger patient in the prednisone alone arm had a dose reduction due to AEs.

Targeted Oncologyspoke with Neal Shore, MD, an author on theEuropean Urologystudy, about the design and goals of the study and the incidence of AEs with abiraterone plus prednisone. In the interview, Shore, the medical director of Carolina Urologic Research Center, also discussed the use of abiraterone in elderly patients and other challenging patient populations.

Targeted Oncology:Can you discuss the differences in corticosteroid-associated adverse events in patients with mCRPC who received prednisone alone or in addition to abiraterone acetate?

Shore:The goals of the study were to look at the long-term adverse event reporting in patients in two very large global phase III trials known as the COU-AA-301 and COU-AA-302. In these studies, we looked at abiraterone 1,000 mg with 5 mg of oral prednisone twice a day versus just oral prednisone alone. The 301 trial was for patients who had received chemotherapy and the 302 trial was for patients that had not yet received chemotherapy.

By looking and reviewing the corticosteroid adverse event-related profiles for several years now in both trials and all arms of the study, we found that the difference between those patients who received abiraterone plus prednisone twice a day versus those who just received prednisone were completely inconsequential when we looked at issues of hyperglycemia, weight gain, or weight increase. This was in patients that were followed for at least a period of 15 months to 2 years, and more in some.

What should oncologists take away from these results?

I think it should really give reassurance to physicians that a low dose of 5 mg prednisone twice a day is safe. The incidence of any challenges were in low single-digit percentages. About 6% of patients had any sort of significant glycemic issues, which were mostly low grade, low incidence and could be easily managed with oral hypoglycemic and diet modifications. Likewise, any issues of weight gain were also managed easily with weight-reduction strategies or occasional diuretic utilization. Essentially the difference between the two arms was inconsequential.

Are there any additional steps planned in this research?

I think it is always good to do long-term studies. Low-dose prednisone not only prevents any potential serologic abnormalities, such as lowering of the potassium, but actually in some patients it improves both their overall energy performance and, in some, their appetite. There are always concerns about chronic use of steroids regarding glucose dysregulation or weight gain, but that has not been seen to be a problem with these agents.

Were there any questions or limitations with this study?

I don&rsquo;t think there were any limitations. We did an earlier phase II study know as the IMAAGEN trial, where we only gave patients 5 mg daily, once a day of prednisone as opposed to twice a day. Those patients also had the same expected efficacy outcomes, and no intolerability or side effect issues.

The labeled indication for abiraterone is 1,000 mg with 5 mg twice daily of prednisone, but the IMAAGEN trial showed us that 5 mg once daily was fine from both a tolerability and safety profile. I can also say in my own personal clinic I am rather routinely starting patients on 5 mg once daily prednisone in conjunction with their 1,000 mg of abiraterone daily.

What is the role for abiraterone in the elderly population (75 and older)?

We are always concerned about any safety effects in the elderly population. They are perhaps immunocompromised, they may have worsening fatigue, more deconditioning, and they are often already on androgen deprivation therapy (ADT). When I am choosing a therapy, I want to make sure that I am not going to exasperate their already baseline fatigue, their lack of appetite, or their diminished participation in extracurricular type activities, specifically their physician activity. Some elderly patients may also have challenges in cognitive function. I think abiraterone is very safe and well-tolerated in that patient population of elderly patients.

Does renal impairment impact how you use abiraterone?

I&rsquo;ve had no difficultly in administering abiraterone to my patients with renal impairment. They tolerated it very well. I am always careful in patients that have hepatic dysfunction, but I don&rsquo;t dose reduce when I initially start patients on abiraterone with renal insufficiency.

Are there any patients who should not be considered for abiraterone?

Probably patients that have class 2 or greater congestive heart failure, which would be associated with very significant fluid retention. That would be my main indication. I&rsquo;ve really had no challenges with patients that had any glycemic control issues, I work very carefully with their endocrinologist and I really can&rsquo;t recall when that was an issue for me. I&rsquo;ve not had problems with either the 5 mg once a day or twice a day doing of prednisone.

What sort of impact hasabiraterone made since it was first approved?

It was the first oral agent to be approved with a survival benefit in the CRPC population post-chemotherapy, and it was the first to be approved in the pre-chemotherapy population. Many clinicians that have had extensive experience taking care of CRPC men, have developed a comfort level in using it. Of course, there have been additional oral therapies that have been approved, and there will be more to come, but there is certainty something to be said for understanding not only the clinical trial data but actual real-world data. I think that it adds to a clinicians ability to discuss very carefully what all our options are for patients with CRPC regarding sequencing or combining with other therapies.

References

1. Fizazi K, et al. Low Incidence of Corticosteroid-associated Adverse Events on Long-term Exposure to Low-dose Prednisone Given with Abiraterone Acetate to Patients with Metastatic Castration-resistant Prostate Cancer.Eur Urol. 2016 http://dx.doi.org/10.1016/j.eururo.2016.02.035
2. Smith, Mathew, Rathkopf, Dana, Peter, F et al. Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years Or Older) Chemotherapy Naive Patients With Metastatic Castration Resistant Prostate Cancer. J Uro.2015 ttp://dx.doi.org/10.1016/j.juro.2015.07.004 Vol. 194, 1277-1284.