Nonmetastatic CRPC Paradigm Bursting With Influx of AR Inhibitors

Winston Tan, MD

All 3 FDA-approved second-generation androgen receptor (AR) inhibitors—apalutamide (Erleada), enzalutamide (Xtandi), and darolutamide (Nubeqa)—have shown an improvement in metastasis-free survival (MFS) in patients with high-risk nonmetastatic castration-resistant prostate cancer (CRPC), said Winston Tan, MD.

"We no longer wait for patients to have metastatic disease before we start treating them," said Tan. "We now have 3 drugs, which have shown that we can prevent metastasis in patients with high-risk disease. When you prevent metastasis, you improve survival."

The approvals of apalutamide, enzalutamide, and darolutamide were based on data from the phase III SPARTAN,¹ PROSPER,² and ARAMIS trials,³ in which each of the AR inhibitors were added to androgen deprivation therapy (ADT) in this patient population. In SPARTAN, results showed a median MFS of 40.5 months with apalutamide (HR, 0.28; 95% CI, 0.23-0.35; P <.0001), and the median MFS was 36.6 months with enzalutamide in PROSPER (HR, 0.29; 95% CI, 0.24-0.35; P <.0001). In the ARAMIS trial of darolutamide, the median MFS was 40.4 months (HR, 0.41; 95% CI, 0.34-0.50; P <.001).

With the use of more sensitive imaging tools to detect evidence of metastatic disease and molecular markers that can identify patients who are most likely to benefit from these agents, the chance of prolonging metastasis is expected to rise, he added.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Tan, a hematologist/oncologist at Mayo Clinic, discussed the influx of treatment options in nonmetastatic CRPC and the modalities that are being used in an effort to ensure their optimal use.

OncLive: How do you use the data from the phase III SPARTAN, PROSPER, and ARAMIS trials to make the best treatment decision for each patient?

Tan: It's a tough call, but there are important toxicities that you have to look for, including falls, osteoporosis, and neurological symptoms. Some of the agents can cause more of those toxicities. It really depends on your patient; patient factors can help you individualize your treatment decisions.

Does darolutamide have a different toxicity profile than apalutamide and enzalutamide?

Based on the [ARAMIS] clinical trial, yes. Darolutamide has shown less toxicity than what has been observed with other drugs. However, you have to consider the total picture, including the cost of the drug, copayments, and other factors in order to choose the right drug for each patient.

Could progression-free survival (PFS)2 be another potential way to distinguish between these agents?

Absolutely. In the past, drugs were approved in the metastatic setting because of their survival benefit. If we can delay that progression, it is very important because if we're delaying the time to metastasis, that could potentially spell “cure” for some of those patients.

Beyond systemic therapies, have imaging tools, such as PET scans, replaced conventional imaging?

It depends on where you practice. In the academic setting, most of these centers have access to PET scans and MRIs. However, some oncologists who practice in smaller towns only have access to CT scans and bone scans. I don't believe that [newer imaging tools] have completely replaced conventional imaging. However, several corporations are building PET centers. In the future, there may be more imaging centers with PET scans, but they will also include different tracers— which are more accurate for locating certain types of metastasis.

Are more sensitive imaging tools needed?

Absolutely; however, right now, they’re not available. Cost can also be an issue. For example, fluciclovine or axumin scans are only indicated for patients with a rising PSA; they're not indicated for patients with metastasis. [These scans] may have value, but there are other scans which are being studied in clinical trials, including the PET prostate-specific membrane-antigen (PSMA) scans, which might change the paradigm in terms of how we treat certain patients with metastatic prostate cancer. It's an exciting time. Many people will be developing their own molecules to study to detect metastatic disease.

What is coming in the pipeline?

We are anticipating drugs that are less toxic; ultimately, better and more appropriate choices for patients. With better molecular testing, we can detect which patients respond to certain treatments and which do not, so we don't treat patients with toxic drugs who aren’t going to benefit. The other change in the way we treat in the future will result from using molecular markers as potential predictors of toxicity.

Are there any agents you are particularly excited about?

One of them is the lutetium PSMA-type molecule. It's exciting that we have a radioisotope molecule. According to preliminary studies, the radioligand has caused disappearance of some bone metastasis or visceral metastasis; that's exciting because we often do not see disappearance of metastasis when we treat patients with metastatic disease.

The important thing I want to emphasize is that even in the advanced setting, African Americans respond the same way to treatment as Caucasians. Therefore, race should not hinder us from treating those patients appropriately.

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 6, abstr 161). doi: 10.1200/JCO.2018.36.6_suppl.161.
2. 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.
3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2019;380(13):1235-1246. doi: 10.056/NEJMoa1815671.