Despite advancements in the treatment of prostate-specific membrane antigen–positive metastatic castration-resistant prostate cancer (PSMA+ mCRPC), barriers continue to challenge the diagnostic process and the patient treatment journey. Neeraj Agarwal, MD, FASCO, Peter R. Carroll, MD, MPH, and William K. Oh, MD, discuss some of these barriers, including the lack of standardized screening methods and patient access, and propose opportunities for advancements in the diagnosis and treatment of patients with PSMA+ mCRPC.

One of the biggest barriers we face in mCRPC is just how quickly the disease can progress. Even though we have a number of effective therapies available now, the reality is that the majority of patients will only have 1 or 2 line(s) of therapy despite all the options available to them. In a real-world analysis, only 61% of patients who received first-line therapy went on to receive second-line therapy, and just 35% received third-line therapy. Even with newer agents and the use of ARPIs earlier in the disease course, that dropout pattern has not really changed. So, the challenge is not only having effective drugs but also making sure that our patients can access them in a timely fashion.

Access itself is another major barrier, especially for someone who is a candidate for ¹⁷⁷Lu-PSMA-617 radioligand therapy. Patients are required to get a PSMA positron emission tomography (PET) scan to confirm eligibility, and that introduces delays. Scheduling, gaining insurance approvals, and coordinating across specialties—all this takes time. Also, not every patient has easy access, especially those living in rural areas and/or underserved populations. For a rapidly progressing disease, this delay really matters.

I think that we have the opportunity here to be much more proactive. For example, when a patient’s prostate-specific antigen (PSA) level is slowly rising on their current therapy, or even when we see a patient for the first time, we can consider germline and somatic testing up front, even before radiographic or symptomatic progression. This way, we already know who is eligible for which treatment. We can also take a similar approach in the case of PSMA PET imaging when it is likely to inform a treatment decision. The key is staying 1 step ahead, reducing delays, and making sure that patients have access to the full sequence of life-prolonging therapies that we have available.

Despite the widespread adoption of PSA screening among urologists and oncologists, it remains controversial. Personally, I am a believer in screening. I think that it decreases cancer death rates. However, the questions remain: How much/often do you screen, and at what cost? The newest approach is early risk-adapted screening (between the ages of 40 and 45 years), which can predict a person’s future risk of prostate cancer. Initial PSA levels and other risk factors allow you to refine how and how often to screen. However, as I tell my patients before they have a biopsy, the biggest risk of screening is being diagnosed with a low-risk prostate cancer, being treated unnecessarily, and then suffering side effects with no benefit.

Instead of proceeding with a biopsy after an elevated PSA level, we now recommend secondary testing, including biomarker testing, magnetic resonance imaging (MRI), or both. MRIs can refine things considerably. In fact, studies have validated the use of MRI-informed diagnostic approaches. One such study, STHLM3-MRI, found that a strategy combining the Stockholm3 (A3P Biomedical AB) diagnostic tool with an MRI-targeted biopsy was able to decrease overdetection while still maintaining its sensitivity. Interestingly, the Stockholm3 tool uses a PSA cutoff that is lower than the US standard to diagnose high-risk prostate cancer (≥3 ng/mL), but it is still able to reduce the number of unnecessary biopsies.

Overall, we are seeing big changes in screening procedures. However, there is still significant variation in screening techniques, and overdetection remains an issue. I think that we must take a very measured approach to diagnosing and treating prostate cancer.

I agree with Dr Carroll that we need to be smarter about screening. I think that risk-stratified screening for prostate cancer is going to have the highest impact. We know that Black men have the highest risk of prostate cancer and death. We also know that men with a genetic risk or family history of prostate cancer are very high-risk individuals. I think that we are getting better at identifying which men are at higher risk, but we also have a lot to learn, including when to stop screening.

The implementation of new knowledge into the community has been a challenge. Things are moving very fast, so it can be hard for providers to keep up. For example, I do not think that we have seen any technique implemented as rapidly as the PSMA PET scan for baseline staging in prostate cancer, including advanced disease. It became available in the United States 3 or 4 years ago, and now it is the only type of imaging I use in advanced disease. Even across the entire spectrum of disease, PSMA PET scanning has become a dominant way to evaluate the status of prostate cancer extent and activity. However, unfortunately, many communities and institutions do not have access, and the need has outweighed the availability, which can make it difficult to get the scans in a timely manner.

Despite the rapid expansion of promising treatment options for prostate cancer, there is no cure-all. Moreover, some patients with mCRPC do not respond to treatment. This is the challenge with translating results from randomized clinical trials into the real world. Although we have a panoply of treatment choices, we need more information to really be able to convey what that optimal therapeutic sequence is, and we really need to better understand which treatments are right for which patients. This is a significant knowledge deficit, but I am hopeful that new tools and educational programs will help.