Earlier Administration of Antiandrogens May Further Delay Disease Progression in Nonmetastatic CRPC

Apalutamide (Erleada), enzalutamide (Xtandi), and darolutamide (Nubeqa) plus androgen deprivation therapy (ADT) are the mainstay of treatment for patients with nonmetastatic castration-resistant prostate cancer (CRPC), and earlier administration of these agents may serve to further delay disease progression in this population, according to Natasha Garg, DO.

All 3 antiandrogen agents were evaluated in similar double-blind, placebo-controlled, multicenter phase 3 trials with only minor differences between them, according to Garg. All agents demonstrated an improvement in metastasis-free survival (MFS), with apalutamide yielding a median MFS of 40.5 months in the phase 3 SPARTAN trial (NCT01946204), enzalutamide demonstrating a median MFS of 36.6 months in the phase 3 PROSPER trial (NCT02003924), and darolutamide eliciting a median MFS of 40.4 months in the phase 3 ARAMIS trial (NCT02200614).^1-3 Moreover, apalutamide and enzalutamide demonstrated median overall survivals (OS) of 73.9 months and 67.0 months, respectively, while darolutamide yielded a 3-year OS rate of 83%.

“Apalutamide, enzalutamide, and darolutamide have revolutionized the treatment landscape for nonmetastatic CRPC,” Garg explained. “These medications [demonstrated] an advantage in MFS, and now OS, in patients who have high-risk nonmetastatic CRPC while still maintaining their quality of life and having acceptable tolerability. Earlier treatment with these agents may be more beneficial in delaying progression of prostate cancer. Every prescriber should be thinking about these medications for this group of patients and realize that these are extremely valuable tools in delaying prostate cancer progression.”

In an interview with OncLive^® during an Institution Perspectives in Cancer webinar on Prostate Cancer, Garg, a medical oncologist and hematologist at City of Hope, discussed the impact of antiandrogens in the treatment of patients with nonmetastatic CRPC, shared advice for choosing among the available options, and projected what the future paradigm might look like.

OncLive^®: Several antiandrogen agents have been approved by the FDA for patients with nonmetastatic CRPC. How have these options impacted care?

Garg: Nonmetastatic CRPC was previously a space with very minimal, to no, treatment options. Three pivotal trials have revolutionized this area, providing [patients with] a multitude of options. The 3 drugs that were looked at were apalutamide, enzalutamide, and darolutamide. Apalutamide was studied in the SPARTAN trial, the PROSPER trial looked at enzalutamide, and the ARAMIS trial looked at darolutamide. All 3 trials were very similar in design, with minor differences. They were all multicenter, phase 3, double-blinded trials that randomized patients in a 2:1 fashion to receive either [one of the aforementioned drugs plus androgen deprivation therapy (ADT)] vs placebo.

The trials included patients with a prostate-specific antigen [PSA] doubling time of less than or equal to 10 months, and ADT was continued for all participants. In all the studies, the patients had conventional imaging [done]—which was computed tomography of the chest, abdomen, pelvis, and a bone scan—and did not have any detectable metastatic disease. Two of the studies, SPARTAN and ARAMIS, allowed for [those with] pelvic nodal disease.

The primary end point for all 3 trials was MFS, which at the time was a novel end point. All 3 drugs were superior to placebo in [terms of] MFS and all had similar results, with about a 2-year delay to metastases compared with placebo. [These data] led to the FDA approval of all 3 drugs. Now, we have OS data, which are positive and demonstrate prolonged survival of approximately 1 year for all 3 drugs.

How do you approach choosing among these agents in clinical practice? What factors do you take into consideration?

We do not have comparative data. [Any] of these drugs are an acceptable option. There are slight differences in safety profile, but there is no major reason to pick 1 drug over the other. Choosing between these antiandrogen agents is not one-size-fits-all [decision]. Treatment [choices] need to be individualized.

For instance, it should not be a knee-jerk reaction to just start these drugs in all patients with nonmetastatic CRPC who have less than a 10-month [PSA] doubling time. For example, if we have a patient who is young and fit, who may have a PSA doubling time of 11 months but has high-risk features like a high Gleason score, I may want to treat this patient [with antiandrogens]. On the other hand, if I have a patient who is frail, elderly, and may have a limited life expectancy, then it may be beneficial from an toxicity and cost standpoint, not to treat this patient and to potentially opt for observation.

I also take into consideration drug–drug interactions, which are prevalent with these medications. Toxicity profiles are important and should be addressed with patients [who have] preexisting comorbidities. The cost of the drug is also something that needs to be recognized.

What are the notable differences in safety profile between these agents? How do you manage these toxicities in practice?

In terms of adverse effects [AEs], what is great about these drugs is that they are all very well tolerated. Taken as a whole, I do not believe that there are notable differences in tolerability. All 3 drugs preserve quality of life for these patients who have been on chronic ADT. It is important to remember that [we don’t have] head-to-head trials with these drugs, but darolutamide did have less fatigue, falls, and fractures [reported with its use], which could mean that it is less likely to cross the blood–brain barrier; [this] could mean less central nervous system AEs, including seizures.

It is also important to consider bone support. We did see fractures as an AE for all of these medications in these trials. Also, we have to remember that these patients have been castrated and will continue these medications longer in all 3 trials. Bone-sparing agent use was low in all 3 trials; this is also an important [factor] to consider.

What is on the horizon for the management of this population?

The utility of novel imaging techniques, [such as] prostate-specific membrane antigen [PSMA] and excellent positron emission tomography [PET] scans [will be important] in the future and will likely redefine our definition of nonmetastatic CRPC, as well as the treatment landscape. More than likely, if you look at these trials, a large majority of these patients would have had metastases picked up on these high sensitivity imaging. However, we still saw [notable] MFS and OS, so there still was a benefit from these drugs.

Now, if you perform a PSMA PET on a patient with nonmetastatic CRPC, you are likely to find metastatic disease. [You would then] potentially reclassify the disease as metastatic, and perhaps treat accordingly. [However], reclassification does not change our evidence. At this time, most of us still use conventional imaging based on the trial data, and do not reclassify these patients who were negative on conventional imaging but may be positive on high-sensitivity scans. Future clinical trials can better clarify the utility of these high-sensitivity scans and tell us how to [better] define treatment decisions.

References

1. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2019;378(15):1408-1418. doi:10.1056/NEJMoa1715546
2. Sternberg CN, Fizazi K, Saad F, et al. 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. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342