Selecting Among AR-Directed Agents in Nonmetastatic CRPC

David Morris, MD, FACS, provides an update on the 3 newest agents available for nonmetastatic castration-resistant prostate cancer treatment and discussed factors to consider when choosing among them.

David Morris, MD, FACS

The emergence of antiandrogen agents in the treatment paradigm of nonmetastatic castration-resistant prostate cancer (CRPC) has revolutionized systemic approaches for patients. Now, the challenge is determining the optimal agent for each individual patient, said David Morris, MD, FACS.

Apalutamide (Erleada) was the first to receive FDA approval in February 2018 for this patient population, a decision that was based on data from the phase III SPARTAN trial. When used in combination with androgen deprivation therapy (ADT), apalutamide showed a significant improvement in metastasis-free survival (MFS) compared with placebo/ADT at 40.5 months versus 16.2 months (HR, 0.28; 95% CI, 0.23-0.35; P <.001).1

Survival data with the agent was then presented at the 2019 ESMO Congress. Treatment with apalutamide/ADT led to a 25% reduction in the risk of death compared with placebo/ADT (HR, 0.75; 95% CI, 0.59-0.96; P = .0197). At a median follow-up of 41 months, the median overall survival (OS) was not yet reached in either arm. Although the trend favored apalutamide, the data were not determined to be of statistical significance.2

“It certainly did favor active drug therapy versus placebo with a median follow-up out to 41 months,” said Morris. “As such, it provides more support for the idea that [apalutamide] will probably show OS benefit if we continue to follow for enough events.”

Another nonsteroidal antiandrogen agent, enzalutamide (Xtandi), was initially approved in 2012 for use in patients with metastatic CRPC who had previously received docetaxel. Then, in July 2018, the agent was approved for patients with nonmetastatic disease as well, after demonstrating a median MFS of 36.6 months when used in combination with ADT versus 14.7 months with ADT alone in the phase III PROSPER trial (HR, 0.29; 95% CI, 0.24-0.35; P <.0001).3

Most recently, darolutamide (Nubeqa), received approval for the treatment of the same patient population based on data from the phase III ARAMIS trial. This agent plus ADT led to a 59% reduction in the risk of metastases or death compared with placebo/ADT (HR, 0.41; 95% CI, 0.34-0.50; 2-sided P <.0001).4,5

With these 3 options now available showing comparable MFS efficacy, the challenge has become determining which drug should be used for an individual patient. According to Morris, that decision might be based not only on clinical toxicities, but financial toxicities as well.

“The real determination of which drug may be best is likely tied to the toxicity profile of the different products,” he explained. “[We need to] look at specific exclusion criteria, such as seizure risk, and their tolerance of the medication. But really, the [choice] may also be [based on] financial toxicity for the patient.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Genitourinary Malignancies, Morris, a urologist at Urology Associates, P.C., provided an update on the 3 newest agents available for nonmetastatic CRPC treatment and discussed factors to consider when choosing among them.

OncLive: Could you speak to the antiandrogen agents that have emerged in the nonmetastatic CRPC treatment paradigm?

Morris: Between the 3 products—apalutamide, enzalutamide, and darolutamide—all 3 have shown similar efficacy data in terms of their primary analysis, which is MFS. All [agents] have shown an approximate 2-year benefit in [MFS] until there's metastasis on imaging. These were all high-risk patients, with quickly progressing disease, had already been on ADT, and did not have any evidence of metastasis on conventional imaging.

Could you expand on the OS data reported for apalutamide at the 2019 ESMO Congress?

These trials were powered initially for MFS, but there has been a lot of interest on secondary outcomes, including OS. The first round of data cuts from all the trials showed a trend for OS but did not reach any statistical significance. There was an update at ESMO for apalutamide data, which showed a further trend to significance but did not yet cross the P value that was required for statistical significance.

You said that all 3 agents have demonstrated similar MFS benefit. How do their safety profiles compare?

[There is some] nuance to the toxicity profiles between the different products and which may be best for which patient. The safety profile for all of them shows a little bit of a fatigue signal; there tends to be a little bit higher risk with enzalutamide and apalutamide than it does with darolutamide.

Some exclusion for seizure risks for enzalutamide [exists] because of early trial experience. [There is a] rash signal that comes to the forefront for apalutamide. However, most of those [adverse events] are manageable, are low-grade, and may not be a [strong enough] reason to avoid [any of the drugs]. The [AEs are] certainly not a reason to stop the medication and switch to another; they can often be managed with active drug therapy.

It’s just very challenging to compare between trials because they're all measured very differently. There are different time intervals for measuring and capturing AEs during the trials, and so you can't even compare the placebo rates between the studies to see if they're equivalent; that makes [things] somewhat challenging. Any patient can have any AE, but for the most part, they're very manageable. With expectations upfront, along with counseling the patient to expect certain things [for each agent], patients tend to tolerate them very well [overall].

Are any additional next-generation antiandrogen agents that are under investigation?

No large trials of any additional antiandrogen inhibitors are ongoing in this space that I'm aware of. I'm sure that compounds are in development that have not yet reached phase III status in terms of trials. We do not have any open, active trials, and we were part of several of these trials. [CRPC is] a disease state that is fairly saturated; not many pharmaceutical companies want to jump into this nonmetastatic CRPC space, which seems to be shrinking with new next-generational imaging techniques. It will be a difficult topic to [have more of these agents] enter the market as fourth- or fifth-line drugs.


  1. Small EJ, Saad F, Chowdhury S, et al. SPARTAN, a phase 3 double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2018;36(suppl 6; abstr 161). doi: 10.1200/JCO.2018.36.6_suppl.161.
  2. Small EJ, Saad F, Chowdhury S, et al. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer [published online September 27, 2019]. Ann Oncol. doi: 10.1093/annonc/mdz397.
  3. 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; abstr 3). doi: 10.1200/JCO.2018.36.6_suppl.3.
  4. Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 7; abstr 140). doi: 10.1200/JCO.2019.37.7_suppl.140.
  5. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi: 10.1056/NEJMoa1815671.