Part 3: Trials Show Efficacy of Enzalutamide and Darolutamide For CRPC

Eleni Efstathiou, MD, PhD​

Section Chief of Genitourinary Medical Oncology

Houston Methodist Oncology Partners

Houston, TX

During a live virtual event, Eleni Efstathiou, MD, PhD, associate professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the phase 3 PROSPER trial (NCT02003924) of enzalutamide (Xtandi) and the phase 3 ARAMIS trial (NCT02200614) of darolutamide (Nubeqa) in patients with castration-resistant prostate cancer.

Targeted Oncology^TM: What is the evidence supporting the use of enzalutamide?

The evidence for the use of enzalutamide comes from the phase 3 PROSPER trial.¹ As I said above, the study design is very similar. Patients with nonmetastatic castration-resistant prostate cancer [nmCRPC], PSA [prostate-specific antigen] doubling time less than 10 months, and baseline PSA over 2 ng/mL were randomized 2:1 to placebo. The end points were also identical; the primary end point was metastasis-free survival [MFS] [and the main] secondary end point was overall survival [OS]. Other secondary end points were [safety, time to PSA progression, time to use of new antineoplastic therapy, PSA response, and] QOL [quality of life].

The median age was 74 years, the PSA doubling time was just below 4 months, and only 10% were on bone-targeting agents at the beginning of the study.

[The median MFS was about 22 months longer with enzalutamide compared with placebo, corresponding to a 71% reduction in the relative risk of radiographic progression or death.^1,2] There was almost a 2-year difference in OS [HR, 0.73; 95% CI, 0.61-0.89; P=.001], which is phenomenal.

I’ve had many discussions regarding how we report adverse events [AEs]. Ideally, certain aspects should be evident from the data set. For example, with fatigue, most data sets focus on reports over grade 3. But a patient with grade 3 fatigue is in bed all day, so it’s important to know the rate of grade 2 fatigue, which is also significant. That was not very clearly reported, nor was the rate of falls.

There weren’t any reports of a rash with enzalutamide.¹ An important thing to point out with this study is the number of deaths due to AEs on trial for any reason. There were 32 cases [3%] in the enzalutamide arm and 3 cases [1%] in the placebo arm. The difference between the 2 is only 2%, but it is a big deal because we’re talking about deaths. In fact, there was a big discussion during the initial presentation of the data set, because there were many patients who died after discontinuing enzalutamide that were not accounted for. It seems that these are mainly cardiovascular events. I’m not pointing the finger at enzalutamide; rather, I believe that there is a need to closely monitor patients who are on prolonged androgen deprivation.

What is the evidence supporting the use of darolutamide?

Darolutamide was the last of these agents to be studied, and data from the phase 1 and 2 trials indicated that it had a good target effect, without the AE. The phase 3 ARAMIS trial confirmed this.

This phase 3 trial had a similar design to the other trials: men with nmCRPC with a baseline PSA over 2 ng/mL, a PSA doubling time of less than 20 months, and an ECOG performance status of 0 or 1, with the same randomization and primary and secondary end points.³ A difference between darolutamide and apalutamide [Erleada] and enzalutamide is that the pills must be taken twice a day, instead of once a day, because of the half-life of the drug. On the bright side, the pills are pretty small.

This trial was done mainly in Europe, but the patient characteristics were similar to the other 2. The median age was 74 years, and the median time from diagnosis was 86 months.³ Between 17% [darolutamide] and 29% [placebo] of patients had regional disease. The median PSA doubling time was 4.4 months. Even though the study design allowed for up to 20 months, this median was very close to the one in the SPARTAN trial [NCT01946204], which was 4.7 months.^3,4 Most patients [76%] had received 2 or more previous hormonal therapy agents, probably bicalutamide and flutamide.

With this study, there were again almost 2 years [22 months] of difference in MFS [HR, 0.41; 95% CI, 0.34-0.50; P<.0001].³ The median follow-up time for this study is much shorter, 17.9 months for MFS and 29 months for OS.^3,5 Despite this shorter follow-up period, the HR for OS is positive [HR, 0.69; 95% CI, 0.53-0.88; P=.03].⁵ With [the SPARTAN, PROSPER, and ARAMIS trials], we have 3 trials that meet all the criteria of read-out, MFS, OS, and all the secondary end points. All the weight is now shifted to the safety.

When it comes to all-grade AEs, there is not yet much of a difference between the 2 arms except for fatigue.³ This is really impressive, but we have to monitor further. These results left me thinking about whether I was going to see the same with my patients, and I have.

_REFERENCES:

_{1. Hussain M, Fizazi K, Saad F, et al. PROSPER: a phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36(suppl 6):3. doi:10.1200/JCO.2018.36.6_suppl.3}

_{2. Sternberg CN, Fizazi K, Saad F, et al; PROSPER Investigators. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892}

_{3. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671}

_{4. Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546}

_{5. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342}