Enzalutamide in Nonmetastatic Castration-Resistant Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•The authors reported an updated overall survival analysis from this phase III trial comparing enzalutamide with placebo in men with nonmetastatic castrate-resistant prostate cancer with a rapidly rising prostate-specific antigen (PSA) level. Median overall survival was longer in the enzalutamide group (67 vs 56 months; HR for death, 0.73; P = .001). The benefit was largely seen across subgroups despite the use of subsequent treatments, including enzalutamide, in the placebo group.

•These findings of superior overall survival add to the previously reported improved health-related quality of life, lower risk of PSA progression, and longer time to subsequent therapy.

– Paul J. Hampel, MD

Oncology 

Written by Oliver Sartor MD

The nonmetastatic castrate-resistant prostate cancer arena has had three trials independently report a survival advantage, and, one of these trials, published in The New England Journal of Medicine, studied enzalutamide and survival of nonmetastatic castrate-resistant prostate cancer. Many of you may be familiar with this particular trial, given that it previously led to an FDA approval for enzalutamide in this space. After a prolonged follow-up, the median overall survival was 67 months with enzalutamide as compared with placebo, which was 56.3 months. That gives a hazard ratio of 0.73 and an unequivocal P-value of less than 0.001. There was no question that the use of enzalutamide in the nonmetastatic castrate-resistant setting led to improved survival.

There are several other aspects that need to be considered. First of all, it is important to recognize that the patients included in this trial all had a PSA doubling time of 10 months or less. The reason that is important is because the FDA approval actually was given within the entire spectrum of nonmetastatic castrate-resistant disease, but the trial was conducted only in those with a PSA doubling time of less than or equal to 10 months. So, that is an important distinction.

Some adverse events were notable. Falls and fractures were more common in the enzalutamide-treated group, and it’s also important to know that similar data for both apalutamide and darolutamide were presented at ASCO, showing an overall survival benefit for each of those agents in the nonmetastatic space.

Taken together, three new trials have been reported for overall survival, and it is important to remember that each of these trials was conducted with a PSA doubling time of 10 months or less. Nevertheless, we have FDA-approved therapies and a survival benefit.

BACKGROUND

Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.

METHODS

In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O'Brien-Fleming-type alpha-spending function.

RESULTS

As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.

CONCLUSIONS

Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).

The New England Journal of Medicine

Enzalutamide and Survival in Nonmetastatic Castration-Resistant Prostate Cancer

N. Engl. J. Med 2020 Jun 04;382(23)2197-2206, CN Sternberg, K Fizazi, F Saad, ND Shore, U De Giorgi, DF Penson, U Ferreira, E Efstathiou, K Madziarska, MP Kolinsky, DIG Cubero, B Noerby, F Zohren, X Lin, K Modelska, J Sugg, J Steinberg, M Hussain

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

[pjoshea13]

Sartor mentions the "PSA doubling time of 10 months or less" three times in his short take-home message, but that is likely to be lost in the media message.

With CRPC & PSADT that low action must be taken, IMO.

But there is no need to rush into treatment if the PSADT is >=18 months & there is no CRPC. I know that some will disagree & men in that group will include many who want immediate treatment. It remains to be seen how that affects survival.

Will there now be a study involving men with non-metastatic PCa [non-mPCa] & no CRPC?

BigPharma seems eager to have drugs typically used in mPCa, used in the much bigger non-CRPC non-mPCa group. It may even rush men into the CRPC state & shorten survival. Just my opinion.

-Patrick