Immunotherapy, Second-Generation AR Antagonists Provide Expansive Utility Throughout Prostate Cancer

Sumit K. Subudhi, MD, PhD

The second-generation androgen receptor (AR) antagonists, darolutamide (Nubeqa), enzalutamide (Xtandi), and apalutamide (Erleada) and immune-oncology (IO) agents, such as checkpoint inhibitors and bispecific antibodies, are generating excitement in prostate cancer, according to Sumit K. Subudhi, MD, PhD.

Current drivers of treatment decisions are the adverse effects (AEs) and central nervous system penetrance (CNS) of the second-generation AR antagonists and the tumor mutational burden (TMB) and microsatellite instability–high/mismatch repair deficiency status of a patient’s tumor for immunotherapy, Subudhi explained, who added that ongoing research is seeking to broaden the role of immunotherapy by combining it with chemotherapy and other checkpoint inhibitors.

“Because all the second-generation agents are given once a day, the AE profiles are going to make the difference,” said Subudhi, an associate professor in the Department of Genitourinary Medical Oncology and Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, in an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on genitourinary malignancies. “We also hope that immunotherapies can lead to curative responses in our patients, which is not something all our other cancer approaches can do in prostate cancer.”

In the interview, Subudhi, discussed the key takeaways from the virtual meeting he chaired, which covered the treatment of patients with nonmetastatic castration-resistant prostate cancer (CRPC), as well as those with metastatic castration-naïve, hormone-sensitive, and castration-resistant prostate cancer.

OncLive^®: How has the utility of immunotherapy grown in prostate cancer since the approval of sipuleucel-T [Provenge]?

Subudhi: There is only one FDA-approved immunotherapy for prostate cancer and that’s sipuleucel-T, which is approved in the setting of metastatic castration-resistant prostate cancer [mCRPC] for patients with asymptomatic or minimally symptomatic disease, meaning that they’re not taking narcotics for cancer-related pain, as an example. In addition, it’s recommended for patients who don’t have visceral metastases like liver metastases, but it’s okay to have lymph node or bone disease, and it’s approved in the first-line setting, meaning prior to docetaxel or second-generation hormonal therapies. It can also be used in the second-line setting after docetaxel or hormone treatment.

We believe that PD-1/PD-L1 and CTLA-4 inhibitors have a role. PD-1 inhibitors like pembrolizumab [Keytruda], are already approved in prostate cancer, but in select patients, those who have a high TMB, or those with defects in the mismatch repair [pathway]. This population probably represents approximately 3% of all prostate cancer cases. These drugs in combination with other checkpoint inhibitors, chemotherapies, or other types of cancer therapies will be more efficacious, and there are ongoing clinical trials evaluating this.

More recently, bispecifics, which have already been FDA approved in [other] cancers, are being used in solid tumors such as prostate cancer, and we’re seeing some exciting activity. It’s too early to tell if these agents have a future, but it’s a promising approach. We hope that immunotherapies can lead to curative responses in our patients, which is not something all of our other cancer approaches can do in prostate cancer.

Bilal A. Siddiqui, MD, gave a presentation on nonmetastatic CRPC treatment, within which he highlighted the phase 3 ARAMIS (NCT02200614), PROSPER (NCT02003924), and SPARTAN (NCT01946204)trials. How have the data from each study illustrated the role of darolutamide, enzalutamide, and apalutamide, respectively?

It’s exciting because, before these studies, there were no treatment options for patients with nonmetastatic CRPC. This was a patient group you just had to watch until they developed metastatic disease.

There are several options [for patients with mCRPC], including chemotherapy, second-generation hormonal therapies, sipuleucel-T—which is a dendritic cell cancer vaccine—and then a radiopharmaceutical agent known as radium-223 dichloride [Xofigo]. For patients with PSMA expression, 177Lu-PSMA-617[has a breakthrough therapy designation from the FDA]. For patients with select DNA defects, such as BRCA1/2 mutations, the PARP inhibitor olaparib [Lynparza] is FDA approved. However, for patients with nonmetastatic CRPC, there had been nothing novel.

These 3 new drugs have a similar mechanism of action because they’re all AR antagonists. It was the first time that the FDA approved drugs not based on overall survival [OS], but on time to metastasis. That allowed for early approval for each of these 3 agents, which is wonderful. Updated data have since shown that [these agents] improve OS, which is exciting.

The question is: Which agent do we choose in clinic? I have a feeling we’re going to use the same approach that we had several decades ago with the first-generation drugs: bicalutamide, nilutamide, and flutamide.

Back then, most clinicians ended up using bicalutamide for a couple of reasons. Number one, bicalutamide had less toxicity. Second was the convenience because it was only given once a day, whereas the other agents had to be given 2 to 3 times a day. All the second-generation agents are given once a day.

The AE profiles are going to make the difference. For example, if someone has neurological issues, such as stroke or a history of seizures, I’m less likely to give enzalutamide or apalutamide because darolutamide is thought to have less central nervous system penetration. If someone has a rash, apalutamide is known to give more of a rash than enzalutamide or darolutamide, so there may be different reasons based on a patient’s medical history that you choose one agent vs the other.

Amado J. Zurita-Saavedra, MD, highlighted the ARCHES trial (NCT02677896) in her presentation on metastatic hormone-sensitive prostate cancer. How have these data informed the utility of androgen deprivation therapy plus enzalutamide in this setting?

Enzalutamide was the first second-generation AR antagonist to demonstrate a survival benefit in the early setting. All these drugs start off in the metastatic castration-resistant setting. Enzalutamide, for example, was FDA approved in the post-docetaxel setting, but you had to receive docetaxel in the castration-resistant setting. Once that got approved, then enzalutamide moved to the pre-docetaxel setting, again in mCRPC, and then that showed a survival benefit. Now, the agent has been moved up to the time when you first find out that you have metastatic disease in the hormone-naïve or castration-sensitive setting, and now the ARCHES trial demonstrated survival benefit there as well.

Did the results of the ODENZA trial (NCT03314324) affect your choice of therapy for patients with mCRPC?

The ODENZA trial was well designed. However, given that there were no statistical differences in efficacy or tolerability between darolutamide and enzalutamide, no conclusions can be drawn. The results of this study do not change my clinical practice.

What data stood out to you from the 2021 ESMO Congress?

The PEACE1 trial [NCT01957436] is the most clinically relevant study presented as it will likely change the standard of care. In this study, the addition of abiraterone acetate [Zytiga] to androgen deprivation therapy and docetaxel with or without radiotherapy improved radiographic progression-free survival and overall survival. I cannot wait until the manuscript is published, because sometimes the devil is in the details.

What will you be keeping your eye on in the future?

It’s going to be important to follow the PSMA-targeting story, both as a theragnostic and diagnostic approach. As a therapeutic approach, we need to figure out when the best time is to use these drugs therapeutically, both in the castration-sensitive setting and in the castration-resistant setting. That’s something that we’ll have to keep an eye on and also try to better identify which patients are more likely to respond to these therapies.