Patients Characteristics, Sequencing Considerations Are Vital in Prostate Cancer Management

Bradley C. Carthon, MD, PhD

The treatment landscape for prostate cancer continues to expand with a broad range of novel hormonal therapies available across different settings, according to Bradley C. Carthon, MD, PhD.

In an interview with OncLive®, Carthon discussed evolving treatment options in both the hormone-sensitive prostate cancer (HSPC) and castration-resistant prostate cancer (CRPC) settings; the nuances of selecting therapies based on disease and patient factors; and the importance of optimal sequencing in the management of prostate cancer.

Carthon is an associate professor of medicine in the Division of Hematology and Oncology at the Emory University School of Medicine and section chief of Hematology and Oncology at Winship Cancer Institute at Emory Midtown in Atlanta, Georgia.

OncLive: How should clinicians approach selecting novel hormonal therapies for metastatic and nonmetastatic prostate cancers?

Carthon: One of the key things about targeted therapies for prostate cancer is that there has been a plethora of options for patients, both in the [metastatic and] nonmetastatic settings—meaning both the hormone-sensitive and castration-resistant settings. There have been even more agents added to the toolbox. It's important that we think about sequencing and genomic testing because many of these items will need to be in such a sequence that we're not repeating or utilizing a similar type of medicine. [We need to ensure that] subsequent lines of therapy [are effective].

How should clinicians approach selecting treatment options in the castration-sensitive setting?

One of the newest things about the castration-sensitive setting has been recent data looking at the presence or absence of disease, as well as what we would consider as high-risk disease in those patients who don't have anything [appear] on scans.

Doubling time for prostate-specific antigen [PSA] under the range of 9 months [can] lead to increased risk of metastases and risk of mortality from prostate cancer. I often tell patients that if their PSA is meandering, we can watch that, but if it is doubling [quickly], then there needs to be some intervention. Androgen deprivation therapy [ADT], which [has been the] standard of care for many years, and the addition of some of the novel hormonal oral agents, such as enzalutamide [Xtandi], are able to [help patients achieve increased] metastasis-free survival intervals, keeping their disease at bay.

How will data from the phase 3 ARANOTE trial (NCT04736199) evaluating darolutamide (Nubeqa) plus ADT in patients with metastatic HSPC inform care?

We have an abundance of riches. A number of trials that have looked at therapies in the hormone-sensitive setting when people have gross metastases on imaging. As one of the oldest agents, a number of trials have been done with abiraterone acetate [Zytiga], including [phase 3] LATITUDE [NCT01715285] and STAMPEDE [NCT00268476] studies.

In addition, enzalutamide has been examined through the [phase 3] ARCHES study [NCT02677896], which showed a survival benefit with [enzalutamide plus ADT]. Lastly, apalutamide [(Erleada) plus ADT was evaluated] in the [phase 3] TITAN study [NCT02489318].

The ARANOTE study looked at darolutamide[plus ADT], and the primary end point was progression-free survival. The data for overall survival are forthcoming and need a little more maturity.

One might ask, with 4 different [hormonal therapy] options, which are we able to utilize? There may be some advantages [observed] with [ARANOTE] regarding some of the adverse effects and the ability for patients to remain on therapy. It is always tough to compare different therapeutics because the studies were not built for head-to-head comparisons. However, there are some promising characteristics both [from ARANOTE] and through some retrospective data that may suggest that darolutamide could be an important player in this realm.

There are some nice retrospective data that can help us sort out which agent is best for which patient. There were some nice data [presented at the 2024 ASCO Annual Meeting] that showed darolutamide has been a bit better regarding patient tolerance and the ability to maintain consistency with dosing.

These [different hormonal therapies] have not been studied head-to-head, so it will take more observation or direct trials and correlates to sort out [which agents are preferable], but it is something to think about when choosing an option for patients.

What are key treatment considerations for patients with HSPC based on the updated National Comprehensive Cancer Network (NCCN) Guidelines?

It boils down to the clinical state of the patient. In patients who have large amounts of disease, visceral organ involvement, and pain crises, these patients have a quick and a real need to have quick [disease] control. The use of triplet therapy with ADT, chemotherapy with docetaxel, and either abiraterone acetate as per the phase 3 PEACE1 trial [NCT01957436] or darolutamide as per the phase 3 ARASENS trial [NCT02799602], would make sense in those patients. There needs to be a rapid control of the clinical situation.

For patients who have either metastases that develop afterward or have lower amounts of disease, those doublet therapies are going to be key. With the ARANOTE trial, we're now up to 4 different agents that can be utilized in that castration-sensitive setting, including abiraterone, enzalutamide, apalutamide, and now, per the ARANOTE trial, darolutamide. There is an abundance of riches. We have to look at all the particular comorbidities for each patient that may lend to the best option for them.

What are some key considerations regarding the management of CRPC?

One of the key points with CRPC is the need to check for genomics early on. We now have a number of studies looking at agents that are effective in the DNA repair pathway. Many of these are in the first line for CRPC. The caveat is that as many of these trials were published and placed into the NCCN Guidelines, whether it be with olaparib [Lynparza] or rucaparib [Rubraca], and even more recently with niraparib [Zejula] or talazoparib [Talzenna], where some combinations [featuring novel hormonal therapies] are going to be utilized [more frequently] in the hormone-sensitive setting. If patients have already had [one of these agents in the hormone-sensitive setting], does coming back to that agent in combination with a PARP inhibitor lend to efficacy [in the castration-resistant setting]?

These are things that have not entirely been sorted out. There will have to be additional studies or observations for the small subsets that may have had those sequential changes. However, if you know someone has those prognostic or actionable mutations early on, [PARP inhibitors] could be utilized in a way that may have more benefit early on vs later in the [treatment] process, where patients have already been exposed to a novel hormonal agent.

How has the shift of some agents to earlier settings impacted the prostate cancer treatment paradigm?

[Treatments] are moving into earlier and earlier [settings]; therefore, we need to know what we're dealing with early on. We're having a multitude of trials that have shown a glimmer of hope, but it's not necessarily effective across the board, so the sequencing in which we utilize available agents is going to be more important.

There have been a number of advances [with prostate-specific membrane antigen (PSMA)–based therapies], and we're excited about that. We're also excited about the fact that some of those agents that use targeted radioligands can also be combined with some of the novel hormonal agents.

If patients are utilizing these novel hormonal agents and develop resistance, there are other agents that are moving up earlier. [We have seen] great data with using PSMA-based therapies such as lutetium Lu 177 vipivotide tetraxetan [Pluvicto] before chemotherapy. All of these agents are moving to earlier [settings]. However, we need to know what actionable targets a patient has and how those can be utilized in the best sequence so that we can utilize all the agents in our toolbox.

Is there any ongoing research you're involved in that you'd like to highlight?

[At Winship Cancer Institute], led by Mehmet Asim Bilen, MD, we're trying to get back into immunotherapy. There are a lot of studies that are focused on activating an immune-cold environment, and the prostate is what we would call a cold environment.

There are some indications in the NCCN Guidelines with regard to the use of checkpoint inhibitors for those who have high tumor mutational burden. We're looking at studies in which bispecific T-cell engager approaches are being utilized to activate a number of immunological targets in the hope that these immune-cold microenvironments within prostate cancer and other tumors are able to be activated in order to use the immune system in those avenues.

Reference

Saad F, Egils Vjaters, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. Published online September 16, 2024. doi:10.1200/jco-24-01798