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Evolving Strategies and Equitable Care in mCRPC
FAQs: Expert Perspectives on Evolving Strategies and Equitable Care in mCRPC 

Released: July 09, 2025

Expiration: January 08, 2026

Alicia K. Morgans
Alicia K. Morgans, MD, MPH, FASCO
Charles J. Ryan
Charles J. Ryan, MD
Neal D. Shore
Neal D. Shore, MD, FACS
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Key Takeaways
  • The efficacy and safety of various emerging therapies targeting cell surface proteins are being investigated for patients with mCRPC and resistance to ARPI therapy in clinical trials.
  • Patient and caregiver education clarifying the importance and potential benefits of clinical trial participation is integral for promoting access to enrollment and diversity of patient populations.
  • 177Lutetium-PSMA-617 is an important therapy in mCRPC associated with improved OS and radiologic PFS in the postchemotherapy setting and improved radiologic PFS in the chemotherapy-naive setting.

In this commentary, Alicia K. Morgans, MD, MPH, FASCO; Charles J. Ryan, MD; and Neal D. Shore, MD, FACS, address key questions posed by the audience during the recent symposium titled, “New Treatments on the Horizon: Cancer Conversations on Novel Mechanisms and Emerging Treatment Options in mCRPC” held during the 2025 American Society of Clinical Oncology annual meeting.

In the current era, what are you most excited about regarding the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), especially the evolving approaches targeting primary and acquired resistance mechanisms?

Charles J. Ryan, MD:
In the current era for our patients with mCRPC, we need to understand the biology of the disease that we are treating. To successfully achieve this, genetic testing needs to be routinely performed in clinical practice. This is important to determine whether a patient is eligible for targeted therapies such as a PARP inhibitor or an immune-directed treatment. Of note, genetic testing also informs us about the underlying mutational status of the patient’s tumor.

I am excited about evolving new approaches in prostate cancer targeting cell surface proteins such as PSMA, STEAP1, TROP2, DLL3 and HER3. This is a whole new avenue to drug development for patients, whether with the use of radioligand therapies, antibody–drug conjugates, or immune-directed therapies. These approaches are already revolutionizing treatment in a number of other cancer types, and it is exciting that we are now investigating these approaches in prostate cancer.

Alicia K. Morgans, MD, MPH, FASCO:
Of note, several of these cell surface proteins are involved in the development of resistance mechanisms to currently available therapies in patients with mCRPC. So, targeting multiple signaling pathways is an appropriate and exciting way to target drug resistance.

Neal D. Shore, MD, FACS:
I agree. Unfortunately, response to androgen receptor pathway inhibitors (ARPIs) does not last forever. Increasing effort is now being directed at the investigation of agents that have novel mechanisms of action. Several antibody–drug conjugates are being investigated (ARX517, FOR46, datopotamab deruxtecan). CAR T-cell therapies such as AZD0754 are also under clinical investigation. Bispecific antibodies that engage T-cells, such as xaluritamig, tarlatamab, and radioligands, are also under investigation for patients with mCRPC.

In addition, the use of novel agents in combination with ARPIs is under investigation in mCRPC. For example, the randomized phase III MEVPRO-1 and MEVPRO-2 trials are investigating mevrometostat, an EZH2 inhibitor, in combination with enzalutamide in mCRPC. MEVPRO-1 is evaluating this combination in patients who have previously received abiraterone, and MEVPRO-2 is assessing the combination in patients with ARPI-naive disease. These approaches are very important to study in patients with mCRPC because the use of such combinations in earlier disease settings may potentially delay or prevent the onset of resistance.

Alicia K. Morgans, MD, MPH, FASCO:
This is particularly important when thinking about resistance mechanisms to ARPIs. Often, this involves AR mutations and/or AR amplification. To evade the pathway being targeted by these inhibitors, prostate cancer cells can engage other pathways. For sustained and continued response therefore, it is important to investigate and take advantage of novel agents that target the potential drug resistance mechanisms, especially those involving cell surface proteins.

What are the important factors to consider when enrolling patients on clinical trials to address the disproportionate absence of impact of novel prostate cancer treatments on patients from ethnic minorities?

Neal D. Shore, MD, FACS:
In South Carolina, we have a high Black and Hispanic population. However,  we do not have a large Asian population. We have recognized that it is very important to enroll patients from non-White populations in clinical trials. This has been encouraged by the FDA and European Medicines Agency. Thus, it is important for healthcare professionals (HCPs) to be flexible and knowledgeable about their conversational approaches given the ethnic diversity of the population of patients with advanced prostate cancer. Knowing and understanding how to communicate with someone who is college educated vs someone who is vocationally trained or someone from rural South Carolina vs someone from the metropolitan Boston area really matters. These are a few dichotomous examples of why HCPs are asked to tailor their patient interactions and why there is emphasis on ethical shared decision-making.

In our world today, authenticity and trust are being doubted and scrutinized via social media, whereby inaccurate information and sometimes conspiracy theories are so easily spread. Patients and their family members, both highly educated and less educated, may come into the clinic and ask questions about the rationale to participate in clinical trials or the use of over-the-counter drugs based on inaccurate information. It is critical to understand how to optimally educate patients and steer them away from this misinformation and toward the importance and benefits that could be derived from their participation in clinical trials. Involvement and utilization of resources from advocacy groups like ZERO Prostate Cancer can be very useful in these circumstances.

In my community-based clinical practice, my approach is to consider every patient as being eligible for enrollment on a clinical trial until proven otherwise. This is very similar to the ethos conducted within academic medical centers.

Charles J. Ryan, MD:
Unfortunately, even though there are multiple novel agents under investigation in clinical trials for patients with mCRPC, we still see disproportionately poor outcomes for certain populations, in particular Black men and other ethnic minorities in the United States. I would like to see more than 5% of patients of ethnic minorities enroll on the available trials. It takes the entire team to successfully match a patient to a trial. We also need to be careful to appropriately educate our patients and their family members about the benefits vs risks of participating in these clinical trials.

Alicia K. Morgans, MD, MPH, FASCO:
I agree. In the past, several clinical trials were conducted with the inclusion of a low population of patients from minority groups. We are doing our best to understand the social determinants of health and cultural factors that affect clinical trial enrolment. We are working to address the long-standing disparities that exist in our medical practices. We are also trying to understand the biological differences that may contribute to the differences seen pertaining to timely disease diagnosis and treatment outcomes in patients from ethnic minorities. We do not yet have a full or complete picture, but we know that there are certain levers that we can pull to continue to move in the right direction. We recognize that this disparity exists, and we are making purposeful strides toward reaching equity in clinical trial enrollment.

In particular, when it comes to advancing the field further, patient education about the importance and potential benefits of clinical trial participation is a great starting point. This may help to ensure that the outcome data from the trials will apply to all individuals with the disease being studied regardless of factors such as ethnicity and/or level of education. In my practice, I consider all available clinical trials and offer trial participation to all my patients who meet the eligibility criteria.

What are your thoughts on the use of radioligand therapies such as 177Lutetium-PSMA-617 for patients with mCRPC?

Neal D. Shore, MD, FACS:
For patients with mCRPC, the standard of care from 2004 to 2010 was docetaxel. Since then, we have seen a cascade of new therapies such as targeted therapies, radiopharmaceuticals, immunotherapies and other parenteral therapies. Radioligand therapies such as 177Lutetium-PSMA-617 are very important in the management of patients with mCRPC. This agent is now indicated for patients with PSMA-positive mCRPC who have been treated with ARPI and taxane-based chemotherapy, and also for those with PSMA-positive mCRPC who have been treated with an ARPI therapy and are considered appropriate to delay taxane-based chemotherapy.

Charles J. Ryan, MD:
I agree that radioligand therapies are very important in the management of patients with mCRPC. There is a survival advantage associated with the use of 177Lutetium-PSMA-617 in the postchemotherapy setting. Its use also yields an impressive radiographic progression-free survival benefit in the chemotherapy-naive setting. So, this agent is here to stay, and it is now widely available in the United States.

One of the key factors to note is that 177Lutetium-PSMA-617 is not a chemotherapeutic agent. It is not given on an every-3-week cycle like docetaxel is administered. There is a different dynamic to the use of radioligand therapies that we are still learning. For some patients, their disease is exquisitely sensitive to this agent, and thus, these patients may receive 2 treatments, responding remarkably well for a long duration of time before retreatment is necessary. So, it is a different modality compared with chemotherapy. Of note, we still have a lot to learn about how to optimally dose radioligands over time for our patients.

Alicia K. Morgans, MD, MPH, FASCO:
We are really scratching the surface with this technology, and 177Lutetium-PSMA-617 is one of the earlier isotopes targeting the prostate-specific membrane antigen. However, I think we will likely see many more radioligand therapies with various isotopes targeting this and other cell surface markers integrated into the treatment landscape for our patients with mCRPC in the near future. This means that patients may be exposed to various radioligand therapies over the treatment course for their disease. Those patients with treatment-sensitive forms of the disease may have long treatment-free intervals before retreatment is needed. As such, I have noticed that patients seem to favor treatment with these agents as they want to keep their lifestyle without much disruption. The quality of life for patients who receive 177Lutetium-PSMA-617 seems to be maintained even though they are receiving intensive therapy for their disease. I think that it is likely that more of these agents will be developed as we continue to see improvements in our ability to keep people safe and well.

Neal D. Shore, MD, FACS:
Across oncology, we are recognizing the importance of treatment intensification, and yet, at the same time, some patients may require treatment deintensification depending upon disease responsiveness and tolerability to treatment. Fortunately, we are now able to use the art of medicine to tailor the use of 177Lutetium-PSMA-617 to the individual patient’s treatment goals.

Your Thoughts
What strategies have you found to be effective to reduce health disparities and improve clinical trial participation among patients of minority populations in your clinical practice?

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In your practice, how often do you discuss enrollment on a clinical trial of novel targeted agents for your patients with mCRPC?

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