Novel AR-Directed Agents Transform Nonmetastatic CRPC Paradigm

Elisabeth I. Heath, MD, FACP, discusses 3 pivotal trials and how they have impacted clinical practice in nonmetastatic castration-resistant prostate cancer.

Elisabeth I. Heath, MD, FACP

Three pivotal trials demonstrating improved metastasis-free survival (MFS) with 3 different oral antiandrogen agents in combination with androgen deprivation therapy (ADT) have led to FDA approvals that have transformed the treatment paradigm in nonmetastatic castration-resistant prostate cancer (CRPC), said Elisabeth I. Heath, MD, FACP.

In February 2018, the phase III SPARTAN trial led to the FDA approval of apalutamide (Erleada) after demonstrating a median MFS of 40.5 months with the agent plus ADT compared with 16.2 months with placebo plus ADT (HR, 0.28; 95% CI, 0.23-0.35;&#8239;P&#8239;<.0001).1

Updated findings of the SPARTAN trial, which were presented during the 2019 ESMO Congress, showed that apalutamide plus ADT demonstrated a 25% reduction in the risk of death compared with placebo/ADT in patients with nonmetastatic CRPC.2,3

Secondly, the phase III PROSPER trial demonstrated similar findings, with an MFS of 36.6 months with enzalutamide (Xtandi) plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35;&#8239;P&#8239;<.0001).4 The FDA approved enzalutamide for this indication in July 2018.

Finally, darolutamide (Nubeqa) was evaluated in patients with nonmetastatic CRPC in the phase III ARAMIS trial, in which the median MFS was 40.4 months with darolutamide versus 18.4 months with placebo (HR, 0.41; 95% CI, 0.34-0.50; P <.0001),4 which led to an FDA approval for this agent in nonmetastatic CRPC in July 2019.

"[This setting is] really defined as men who are at a castrate level of their testosterone with rising prostate-specific antigen while [they are] on ADT, but [there is] no evidence of metastasis on standard imaging," explained Heath on the uniqueness of this setting.

In an interview during the 2019 OncLive® State of the Science Summit™ on Genitourinary Malignancies, Heath, a professor of oncology, associate center director of Translational Sciences, lead of the Genitourinary Oncology Multidisciplinary Team, medical director of the Infusion Center, and director of Prostate Cancer Research at Karmanos Cancer Institute, Wayne State University School of Medicine, discussed these 3 pivotal trials and how they have impacted clinical practice in nonmetastatic CRPC.

OncLive: How has nonmetastatic CRPC treatment transformed?

Heath: Nonmetastatic CRPC is a very unique space, but it is a little bit of a frustrating space because you want to treat [patients] with something, but you are not sure where the cancer is. Recent developments have led to 3 FDA approvals, which is quite exciting.

MFS is a newer endpoint that needed to be developed because this is not a group where overall survival (OS) makes a lot of sense. The FDA does recognize MFS; it is a new nuance in how we think about drug development in this particular space.

Could you discuss the 3 antiandrogen agents that are now available?

The National Comprehensive Cancer Network (NCCN) has recognized 3 medications: apalutamide, enzalutamide, and darolutamide. They all are approved based on 3 similarly designed phase III studies. Apalutamide was explored in the SPARTAN study, enzalutamide was studied in the PROSPER study, and darolutamide was tested in the ARMAIS study.

All of those studies enrolled at least 1400 to 1500 patients who either had the medication or placebo in a 2:1 randomized fashion. The key point is that the patients were men who had standard imaging with a bone scan or CT scan, no evidence of cancer, and rising prostate-specific antigen (PSA), but at a doubling time of less than 10 months. It was a more aggressive group.

The trials had the primary objective of MFS with a slew of secondary objectives, including OS. Then, all of [the results from these trials showed] that men can benefit from these agents compared with placebo.

Are there any notable differences between these studies?

Each trial is unique in itself; the differences are not necessarily in the trial design. However, [SPARTAN] allowed for abiraterone acetate (Zytiga) at crossover; that may or may not impact the overall numbers later on.

The differences dealt more with the adverse events (AEs) with each drug, because these are relatively asymptomatic men. The patients and practitioners [get] worried that the [PSA] is going up and we can't find the cancer. It's a more engaged group, but for those of us who treat men where their PSA is starting to skyrocket, getting the nuance of each particular drug is important.

You mentioned that toxicities are an important distinguishing factor between the 3 drugs. How do you approach patient selection?

That is a tough question, because the data are reported in terms of what the AEs were. They don't always overlap.

The idea that some of these agents can cause fatigue is not new, because [this class of drugs is] available in metastatic castration-resistant prostate cancer. Many of us have some experience treating patients in a more advanced setting.

In terms of the falls and fracture risk, the ≥75-year-old group of men had a slightly higher incidence compared with placebo. We wonder if that is a balance issue, or if there is some neurologic toxicity.

Darolutamide, for example, did show [lessened neurologic toxicity], which is perhaps due to its unique mechanism of action. Darolutamide doesn't have such a big blood—brain barrier impact, so perhaps the neurologic toxicities [rates are lower].

In the PROSPER trial, there were more cardiovascular deaths, which remains somewhat unexplained. Perhaps if a patient already had cardiovascular compromise, enzalutamide may not be the best option [for them].

The great part is that we have 3 different agents [to consider], and we can tailor those treatment decisions based on the patient.

What is your take-home message to colleagues?

Be aware that there are drugs actually approved in this space. The SPARTAN study and the PROSPER study were just published in 2018, and the ARAMIS study was [published in] 2019. If you're not treating and thinking about prostate cancer patients like some of us spend our lives doing so, you may not be aware that there are NCCN-supported medication available to offer to patients. Recognizing that that exists is a wonderful next step of awareness for your patient.


  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).&#8239;J Clin Oncol. 2018;36(suppl 6s; abstr 161). doi: 10.1200/JCO.2018.36.6_suppl.161.
  2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in patients with nonmetastatic castration-resistant prostate cancer: updated results from the phase III SPARTAN study. Annal Oncol. 2019;30(suppl_5):v325-v355. doi: 10.1093/annonc/mdz248.
  3. Small EJ, Saad F, Chowdhury S, et al. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019;0:1-8. doi: 10.1093/annonc/mdz397.
  4. 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).&#8239;J Clin Oncol.&#8239;2018;36(suppl 6S; abstr 3). doi: 10.1200/JCO.2018.36.6_suppl.3.
  5. 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 7s; abstr 140). doi: 10.1200/JCO.2019.37.7_suppl.140.