Broader ARPI Arsenal Enables Personalized, Cost-Conscious Treatment Selection in Prostate Cancer

Nataliya Mar, MD

The expanding prostate cancer treatment armamentarium, which encompasses radioligand therapies, androgen receptor pathway inhibitors (ARPIs), and PARP inhibitors, offers greater flexibility in selecting a preferred regimen that accounts for patients’ comorbidities and treatment-related costs, according to Nataliya Mar, MD.

“Generally speaking, we have 4 choices in terms of ARPIs that are currently on the market,” Mar said. “The biggest factor that affects choice is physician comfort, what they're familiar with, and what they have historically used.”

There are currently 4 FDA-approved ARPIs for the treatment of prostate cancer: abiraterone acetate (Zytiga), apalutamide (Erleada), darolutamide (Nubeqa), and enzalutamide (Xtandi). In 2011, the FDA approved abiraterone acetate with prednisone for patients with metastatic castration-resistant prostate cancer (mCRPC); the agent was subsequently approved for metastatic high-risk castration-sensitive prostate cancer (mCSPC) in February 2018.1 In February 2018 and September 2019, the FDA approved apalutamide for the treatment of patients with nonmetastatic CRPC (nmCRPC) and mCSPC, respectively.2,3 Darolutamide won approval from the FDA in July 2019 and August 2022 for the treatment of patients with nmCRPC and metastatic hormone-sensitive prostate cancer (mHSPC), respectively.4,5 In December 2019, enzalutamide was approved by the FDA to treat patients with mCSPC.6

During an interview with OncLive®, Mar discussed the shift towards using ARPIs in earlier settings, factors that influence ARPI selection, reasons for not rechallenging with ARPIs following disease progression, and the role of PARP inhibitors in the prostate cancer treatment paradigm.

Mar is an associate professor in the Division of Hematology/Oncology, at the University of California, Irvine Chao Comprehensive Cancer Center.

OncLive: How has the role of ARPIs changed with agents moving into earlier treatment lines in prostate cancer management?

Mar: In recent years, ARPIs have migrated to a much earlier setting. Our initial experience with these drugs has been in the pretreated mCRPC space. They then came into the untreated mCRPC space. Now we're using them much earlier. For example, they have become a standard of care for patients who have mCSPC, and they're used as double therapies in combination with androgen deprivation therapy [ADT]. This is very standard; everyone who presents with mCSPC nowadays gets at least a doublet therapy containing an ARPI. More recently, there are data [showing] that these agents are active in the biochemically recurrent space. There was the phase 3 EMBARK study [NCT02319837], which showed the effectiveness of one particular agent in this space, enzalutamide. This agent gained FDA approval [in November 2023]. To summarize, we now routinely use these agents much earlier compared with when they first entered the market.

How do you approach the selection of ARPIs?

A common factor to consider [when selecting an ARPI] is insurance reimbursement. These agents are oral and they're expensive, so sometimes the insurance dictates which agent to use. Some of these have been on the market long enough that they are now generic, so their price is more affordable.

Another factor influencing the decision is patients’ comorbidities, and how you match that with the toxicity profile of each drug. For example, one of the agents to choose from is abiraterone acetate, which is typically given in combination with a low-dose steroid. For some patients, steroids are not a good idea. These are patients who have, for example, osteoporosis or diabetes, or those who are older. This could dictate what [is feasible] to use. Another example is the risk of seizures with enzalutamide. If a patient has a seizure history, you might not want to use that agent. One treatment is not superior to others in terms of effectiveness.

Are there any circumstances in which you would consider ARPI rechallenge for a patient with prostate cancer?

In general, I do not rechallenge with an ARPI after failure on an ARPI, because that's a common resistance mechanism within prostate cancer cells that develops after someone has been exposed to an ARPI. These drugs just do not work after a [patient progresses on] a similar agent. Additionally, when we rechallenge with another drug, it can be costly. We also want to consider the cost of health care right now, and most of the time, [ARPI rechallenge] doesn't work.

However, there have been recent developments [with this concept], which are still in the experimental phase. This is by no means ready for use in the clinical setting, but bipolar ADT [is being developed] as a mechanism for potentially resensitizing the tumor to another ARPI. The pivotal phase 2 trial that described this approach is called the TRANSFORMER trial [NCT02286921]. However, this is still an investigational approach and not quite ready [for prime time].

How have PARP inhibitors improved the prostate cancer treatment paradigm?

PARP inhibitors have been a breakthrough in the prostate cancer world. They added to our armamentarium of therapies we can utilize for our patients. Mutations in the DNA damage repair pathway, it turns out, are fairly common in prostate cancer, both in the somatic setting and the germline setting. This gave us an extra treatment option that's quite effective for our patients with prostate cancer [displaying] susceptible mutations.

Are there any novel targets that could lead to the development of other targeted therapies in prostate cancer?

There are many ongoing trials evaluating a variety of mutations known to exist in prostate cancers. None of these agents are FDA approved yet. We also have many agents in development that are not necessarily mutation-based, but are based on proteins that are expressed on the surface of prostate cancer cells. One example of this is lutetium Lu 177 vipivotide tetraxetan [Pluvicto], and many others following [this radioligand therapy] that are currently being evaluated in trials. This is an exciting time where lots of therapies are in the works, and we're excited to see what comes of that.

References

1. FDA approves abiraterone acetate in combination with prednisone for high-risk metastatic castration–sensitive prostate cancer. FDA. Updated February 8, 2018. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abiraterone-acetate-combination-prednisone-high-risk-metastatic-castration-sensitive
2. FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. FDA. Updated May 3, 2018. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-non-metastatic-castration-resistant-prostate-cancer
3. FDA approves apalutamide for metastatic castration-sensitive prostate cancer. FDA. Updated September 18, 2019. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-metastatic-castration-sensitive-prostate-cancer
4. FDA approves darolutamide for non-metastatic castration-resistant prostate cancer. FDA. Updated July 31, 2019. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer
5. FDA approves darolutamide tablets for metastatic hormone-sensitive prostate cancer. FDA. August 5, 2022. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-tablets-metastatic-hormone-sensitive-prostate-cancer
6. FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. FDA. Updated December 17, 2019. Accessed April 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-metastatic-castration-sensitive-prostate-cancer