Antiandrogens Continue to Be Focus of Nonmetastatic CRPC Treatment

Atish D. Choudhury, MD, PhD

Despite the differences in safety profiles, darolutamide (Nubeqa), enzalutamide (Xtandi) and apalutamide (Erleada), yield similar overall survival (OS) benefit in patients with nonmetastatic castration-resistant prostate cancer (CRPC) who are also continuing androgen deprivation therapy (ADT), according to Atish D. Choudhury, MD, PhD, who added that focal therapy might also play an important role in this space.

Three pivotal trials demonstrated improved metastasis-free survival (MFS) with 3 different antiandrogen agents in combination with ADT. Results from the phase 3 SPARTAN trial led to the February 2018 FDA approval of apalutamide; the agent plus ADT led to a median MFS of 40.5 months versus 16.2 months with placebo/ADT.¹ Updated findings showed that apalutamide/ADT also resulted in significantly longer median OS versus placebo/ADT at 73.9 months versus 59.9 months.²

The phase 3 PROSPER trial showed similar findings with enzalutamide plus ADT, with a median MFS of 36.6 months versus 14.7 months with placebo/ADT; this led to the July 2018 FDA approval of the agent.³ Lastly, results from the phase 3 ARAMIS trial with darolutamide/ADT showed a median MFS of 40.4 months versus 18.4 months with placebo/ADT, which led to the July 2019 FDA approval of darolutamide in this patient population.⁴

“The take-home message is that nonmetastatic CRPC reflects a variety of clinical states, such as local recurrence versus nodal recurrence, etc. The agents available for nonmetastatic CRPC have been associated with benefit in MFS and overall survival (OS) in patients with a prostate-specific antigen (PSA) doubling time of 10 months or less. As such, we should certainly use these agents in that setting,” said Choudhury. “Then, we should think a little more broadly about focal therapy, as this may also be beneficial to these patients. We also must determine how to manage the safety profiles and decrease associated costs. [The goal is to] prolong the patient's life while maintaining quality of life to the highest degree possible.”

In an interview with OncLive during an Institutional Perspectives in Cancer webinar on Prostate Cancer, Choudhury, the co-director of the Prostate Cancer Center and a senior physician at Dana-Farber Cancer Institute, as well as an instructor in medicine at Harvard Medical School, shed light on the nonmetastatic CRPC treatment landscape and notable ongoing trials examining antiandrogens in different settings.

OncLive: Could you shed light the pivotal data with antiandrogen therapies that have read out in the nonmetastatic CRPC space?

Choudhury: Three major trials examined antiandrogen therapy in nonmetastatic CRPC. The PROSPER trial assessed enzalutamide, the SPARTAN trial assessed apalutamide, and the ARAMIS trial assessed darolutamide. They all had similar eligibility criteria, along with similar outcomes with regard to MFS and OS. Results from these studies demonstrated that all 3 agents had an OS benefit when followed over time. The differences [between the agents can be seen] in the safety profiles. Certainly, the choice of the agent will depend on insurance coverage and cost.

What is nonmetastatic CRPC? It actually represents a variety of different states. This cancer is castration resistant, but the location of the disease varies from patient to patient. In some patients, it represents local recurrence while in others it represents a recurrence involving pelvic lymph nodes, which were allowed on all 3 studies. Finally, in some patients, it involves more diffuse micrometastatic disease that may or may not be detectable on novel imaging. These new agents are certainly important tools in the management of [patients with] nonmetastatic CRPC. However, I believe novel imaging and approaches for focal therapy also might play a role, as well.

Could you expand on some of the most significant findings from the ARAMIS, PROSPER, and SPARTAN trials?

The ARAMIS, PROSPER, and SPARTAN trials are very similar in terms of eligibility. All patients had nonmetastatic CRPC, meaning that metastatic disease has never been shown on conventional imaging. They also must have had a castrate level of testosterone. Moreover, in the PROSPER and ARAMIS trials, patients were allowed to have pelvic lymph nodes up to 1.5 cm in size. In the SPARTAN trial, patients could have lymph nodes up to 2 cm in size. Patients were randomized 2:1 to receive either darolutamide, enzalutamide, or apalutamide, depending on the trial, versus placebo, in addition to ADT. All studies were placebo-controlled, and the primary end point was MFS.

All 3 trials required a PSA doubling time of less than 10 months, so those findings don't necessarily apply to patients with a longer PSA doubling time. All trials reported a variety of secondary end points, such as the time to next therapy, time to symptomatic progression, and OS.

All 3 studies demonstrated an OS advantage with a hazard ratio of about 0.7 for all 3. All 3 agents are FDA approved in this indication and can certainly be tried. The differences [between the agents] can really be seen with regard to their safety profiles. It was discovered that enzalutamide might have a little more impact in terms of fatigue and risks of fractures and falls. Apalutamide has a risk of rash, which the other 2 agents don't have, as well as hypothyroidism, which is generally asymptomatic and not a problem for patients. Darolutamide seems to be better tolerated than the other 2 agents, although there is still some increased fatigue with this agent compared with placebo; it does not carry the same risk of fractures, falls, and rashes as the other agents. Again, all 3 agents are reasonable options, so it really comes down to the cost and insurance coverage.

How do you approach using these 3 agents in your own practice?

All 3 agents are quite reasonable options to choose from. The first decision to make is to determine whether the patient is warranted for the treatment at all. Certainly, I do use PSA doubling time as a consideration because patients with longer PSA doubling time may not require intensification of treatment beyond ADT. In terms of patients with shorter PSA doubling time, my common practice is to get imaging. In cases where imaging is covered by their insurance, I would request novel PET imaging. If those results do demonstrate focal disease, then I'll often use the systemic agent in conjunction with focal therapy to the sites of disease. If the imaging does not demonstrate sites of disease, then I'll use the agent, along with ADT, generally until progression.

However, these studies don't answer whether it's safe or reasonable to discontinue these agents. For example, if a patient starts with these agents and has a very profound and prolonged response, is it reasonable to discontinue treatment to give the patient a break for reasons such as quality of life, or should these agents be continued until progression as was done in the trials?

Could you highlight additional ongoing research with these agents?

We are looking forward to the results of the trials that are studying these agents in the context of high-risk localized disease, in both the neoadjuvant and adjuvant settings. The PROTEUS trial, for example, will assesses neoadjuvant and adjuvant apalutamide. There is also the ENZARAD trial, where enzalutamide is examined in combination with ADT for localized disease in conjunction with radiation. There is the ATLAS trial, which will look at apalutamide in the same setting, and there is also an upcoming trial called DASL-HiCAP, which will assess darolutamide in the same setting.

I mentioned those particular studies because, again, much of the nonmetastatic CRPC space consists of patients with local recurrence of their disease. As such, if you have more aggressive and effective treatments for localized disease at the beginning, then hopefully you can avoid the need for the use of these agents down the line. Ultimately, more patients will be cured, and we will have less patients with nonmetastatic CRPC in the future.

References

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 6s):161. doi:10.1200/JCO.2018.36.6_suppl.161
2. Saad F, Small EJ, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer. J Clin Oncol. 2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516
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 6S):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 7s):140. doi:10.1200/JCO.2019.37.7_suppl.140