A rising tide that lifts all boats: PSMA-PET and genomic testing for prostate cancer

Daniel Canter, MD, specializes in urologic cancers and leads Georgia Urology’s Advanced Prostate Cancer team and clinical research efforts.

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Advances in imaging, integration of genomics, and expanding treatment options enable more accurate staging, deeper molecular characterization, and earlier, more targeted treatment, but technology alone isn't enough. As the tools and treatment options become more sophisticated, advanced prostate care is becoming a more specialized area of urology so that clinicians can keep pace.

PSMA-PET imaging

Historically, men with advanced or suspected advanced prostate cancer would undergo imaging with a CT scan and a bone scan. CT scans and bone scans are useful but relatively nonspecific and can miss smaller or earlier metastatic lesions. As a result, some men who appeared to have localized disease based on conventional imaging could actually turn out to have occult metastatic disease that was not identified at the time of treatment. PSMA-PET has greater sensitivity for prostate cancer lesions, so it can reveal metastatic disease that conventional imaging cannot detect.

Metastatic disease can be present despite a relatively low PSA [prostate-specific antigen]; prostate cancer does not necessarily continue to produce PSA as it progresses. In some cases, there may be little reason to suspect metastatic disease initially. When conventional imaging is ordered, it can miss that first lesion entirely, allowing the disease to progress until the PSA rises or subsequent imaging shows more extensive disease.

What's been really amazing with PSMA-PET imaging for prostate cancer is that it’s very specific for picking up prostate cancer, finding lesions at very low PSAs that surely would not have been seen with conventional imaging.

PSMA-PET imaging accomplishes a more accurate picture of the disease at an earlier point in the disease timeline. From the outset of diagnosis, it affects treatment. Earlier identification creates an opportunity to use multimodal therapy sooner, potentially treating both the known site of metastatic disease and other cancer cells that may not yet be detectable on other imaging, in turn delaying the development of additional metastatic lesions. If metastatic disease is identified, treatment can be directed appropriately from the beginning rather than waiting for the disease to become more extensive.

In many cancers, routine imaging is part of diagnosis and treatment, and CT, PET, MRI, or other imaging are incorporated into ongoing surveillance. On the other hand, a prostate cancer patient might undergo diagnostic imaging, especially if metastatic disease is suspected, and then receive little or no subsequent radiologic evaluation if the PSA remains low. Applying the same rules as other cancer surveillance to prostate cancer is where there is room for opportunity. Rather than treating imaging as static baseline testing, clinicians can use it at appropriate points during the disease timeline to evaluate treatment response and look for active or recurrent disease.

Genomic testing

Genomic testing is becoming increasingly relevant in medicine. These tests can unveil mutations or other changes associated with prostate cancer, and if a patient has a specific mutation, there may be a targeted therapy from which he is more likely to benefit than a patient without that mutation.

There was less urgency in the past to perform this testing early because actionable results often did not become relevant until later in the disease course. If a treatment would not be considered until years after the initial diagnosis, there was less reason to make genomic testing an immediate part of the treatment decision. We aren't seeing through that lens anymore. PARP inhibitors, for example, are now being used earlier in metastatic prostate cancer, and there are also treatments being developed or used based on other specific molecular characteristics, such as PTEN deficiency. Earlier timing of genomic testing is becoming more important at all stages of the disease process.

As treatment decisions become more biomarker-driven and technology evolves, understanding when to order testing and how to interpret the results is increasingly important for urologists involved in prostate cancer management. Waiting until much later in the disease course may mean missing an opportunity to use that information to optimize outcomes, affect the disease course, delay metastases, and potentially improve longevity and quality of life.

Changing the treatment timeline

Historically, there were fewer treatment options and less routine imaging available to clinicians managing advanced prostate cancer, particularly for men with metastatic disease. Often, regardless of disease burden, the approach to these men was one of benign neglect. This was partly due to the older age of patients and partly because few therapies existed until the 2010s. Standard treatment was androgen deprivation therapy, which [involves] lowering a man's testosterone and would delay the progression of advanced prostate cancer for a number of years until, most of the time, the man would die of something else, even with metastatic disease.

That treatment landscape has changed substantially. Androgen deprivation therapy alone is no longer the only systemic option. Clinicians now have androgen receptor pathway inhibitors, PARP inhibitors, radioligand therapy, and other treatments based on the molecular characteristics of the cancer. At the same time, PSMA-PET and genomic testing are increasingly becoming available and more accessible.

PSMA-PET and genomic testing are separate technologies, but they inform the same clinical questions: knowing what disease is actually present and what targeted treatment options are available for the individual. Men with metastatic disease can be undertreated if their cancer is mistaken for localized disease. At the same time, accurate staging can prevent a man with truly localized disease from receiving treatment intended for more advanced cancer, along with the associated toxicities.

If PSA becomes undetectable and imaging shows no active disease, therapy can be deintensified and followed by biochemical and radiologic surveillance. There is a balance of treatment benefits against the risk of significant [adverse events], which, if therapy is continued too long, may ultimately pose a greater threat to lifespan than the prostate cancer itself.

The same principle applies later in the disease course, when imaging and biochemical information can help determine whether treatment deintensification or continuation is appropriate. Prolonged treatment can have significant adverse effects, and in some patients the effects of long-term therapy can become a greater concern than the prostate cancer itself.

Keeping pace

Prostate cancer care has changed substantially over the last decade. As treatment becomes more genomically driven, understanding when to order germline testing, when to pursue somatic profiling, and how to interpret the results is becoming an increasingly important skill for urologists involved in prostate cancer management.

Technology advancement and accessibility will have a significant and clinically meaningful impact on patients’ lives, longevity, and quality of life, as well as on the lives and well-being of their families.

Specialization is pivotal given the complexity of advanced prostate cancer and because prostate cancer is only one part of what a general urologist manages. With the stakes involved and the number of available treatments continuing to increase, having providers who focus specifically on advanced disease can help provide better patient care and keep other urologists up to date with expanding diagnostic and treatment options.

As helpful as these newer approaches are, there are still practical barriers to address. Access to PSMA-PET is generally good, but insurance coverage can be inconsistent. Some payers still require conventional imaging, such as a CT scan and bone scan, before approving PSMA-PET. In some cases, a patient may have a negative CT and bone scan results and then have the PSMA-PET denied because those conventional scans were negative. This is problematic, to say the least, when the purpose of PSMA-PET is to identify metastatic disease that conventional imaging may not detect. For genomic testing, the greater issue can be out-of-pocket cost and, again, what a patient's insurance will cover.

Despite those barriers, the potential and growing availability of more precise imaging, molecular information, and treatment options will help guide clinical decision-making on when to intervene, how aggressively to treat, and how closely to monitor disease progression as well as remission. Prostate cancer shouldn't necessarily be managed as “diagnose it, treat it, check the PSA, and move on.” We have entered an era where accurate staging and molecular information can change what we do for a prostate cancer patient much earlier in the disease course. Obtaining the right information early enough and repeatedly reassessing the disease with imaging and biochemical information can change the patient's treatment trajectory and generate a greater quality of life.