By Gilang Cahya 
A new study led by researchers at the UCLA Health Jonsson Comprehensive Cancer Center has found that many cases of high-risk nonmetastatic hormone-sensitive prostate cancer may be more advanced than previously thought.
The groundbreaking research, published in the esteemed journal JAMA Network Open, has revealed a significant underestimation of metastatic disease in men diagnosed with high-risk, nonmetastatic hormone-sensitive prostate cancer (HSPC). Utilizing advanced Prostate-Specific Membrane Antigen-Positron Emission Tomography (PSMA-PET) imaging, the study found that nearly half of these patients, previously classified as nonmetastatic by conventional imaging techniques, actually harbor metastatic disease. This discovery has profound implications for how prostate cancer is staged, treated, and understood, potentially reshaping treatment paradigms and offering new avenues for patients.
The Limitations of Conventional Imaging
For decades, the staging of prostate cancer has relied on a combination of clinical assessments, biochemical markers like Prostate-Specific Antigen (PSA) levels, and anatomical imaging modalities such as computed tomography (CT) scans and bone scans. While these methods have been instrumental in guiding treatment decisions, they have inherent limitations, particularly in detecting small, disseminated tumor deposits. Conventional imaging primarily provides structural information, showing the size and location of tumors, but struggles to identify microscopic spread or assess the biological activity of cancerous cells.
This limitation becomes particularly problematic in high-risk prostate cancer. This category encompasses tumors that are aggressive, have a higher chance of recurrence after initial treatment, and are more likely to spread. Historically, patients classified as having nonmetastatic disease, even within this high-risk group, were treated with approaches assuming the cancer was confined to the prostate or its immediate surroundings. This often involved surgery or radiation therapy to the prostate, sometimes supplemented by androgen deprivation therapy (ADT), a cornerstone treatment that lowers testosterone levels to slow cancer growth.
PSMA-PET: A New Era in Prostate Cancer Detection
The advent of PSMA-PET imaging represents a paradigm shift in the ability to visualize prostate cancer. PSMA (prostate-specific membrane antigen) is a protein that is highly expressed on the surface of prostate cancer cells, including both primary tumors and metastatic lesions. PSMA-PET imaging utilizes specially designed radioactive tracers that bind to PSMA. These tracers emit positrons, which are detected by the PET scanner, creating detailed, three-dimensional images that highlight areas where prostate cancer cells are present.
Unlike conventional anatomical imaging, PSMA-PET offers functional and molecular information, visualizing the biological activity of the cancer. This allows for the detection of even small metastatic deposits that may be undetectable by CT or bone scans. The increased sensitivity and specificity of PSMA-PET have the potential to dramatically improve the accuracy of cancer staging, leading to more precise treatment planning and potentially better patient outcomes.
The EMBARK Trial Context: A Retrospective Lens
The UCLA study was designed as a post hoc, retrospective cross-sectional analysis of data from 182 patients who had participated in the EMBARK trial. The EMBARK trial itself was a pivotal, large-scale, randomized, double-blind, placebo-controlled clinical trial that investigated the efficacy of enzalutamide, a potent androgen receptor inhibitor, when added to ADT in men with metastatic hormone-sensitive prostate cancer (mHSPC). However, a subset of patients in EMBARK were those with high-risk nonmetastatic disease who were considered eligible for the trial based on conventional imaging criteria, suggesting no evidence of distant spread.
The EMBARK trial, published in the New England Journal of Medicine in 2018, demonstrated a significant improvement in metastasis-free survival when enzalutamide was added to ADT in men with mHSPC. While this trial was transformative for the management of metastatic disease, the UCLA researchers hypothesized that the criteria used for patient selection, relying on conventional imaging, might have inadvertently included patients who actually had occult metastatic disease.
Key Findings: A Stark Revelation
The UCLA study’s findings were striking. When the 182 patients from the EMBARK trial cohort were re-evaluated using PSMA-PET imaging, a substantial number were found to have metastatic disease that had been missed by conventional imaging. Specifically, PSMA-PET detected cancer metastases in an astonishing 46% of these patients. This means that nearly half of the individuals who were classified as having nonmetastatic disease based on CT scans and bone scans actually had cancer that had spread to distant sites.
Further analysis revealed the extent of this underestimation. The study reported that 24% of the patients in the cohort showed five or more metastatic lesions that had been completely overlooked by traditional imaging methods. This highlights not only the presence of metastatic disease but also its potential significance in terms of tumor burden.
Dr. Adrien Holzgreve, a visiting assistant professor at the David Geffen School of Medicine at UCLA and the first author of the study, commented on the findings: "We anticipated that PSMA-PET would detect more suspicious findings compared to conventional imaging. However, it was informative to uncover such a high number of metastatic findings in a well-defined cohort of patients resembling the EMBARK trial population that was supposed to only include those without metastases." This statement underscores the surprising degree to which conventional imaging fell short in accurately assessing the extent of disease in this high-risk group.
Implications for Treatment Decisions and Outcomes
The implications of these findings are far-reaching and directly impact clinical decision-making. Accurate staging is the bedrock of effective cancer treatment. If a patient is incorrectly classified as nonmetastatic when they have disseminated disease, they may not receive the most appropriate and potentially curative therapies.
For patients with high-risk nonmetastatic prostate cancer who are found to have occult metastases via PSMA-PET, this could mean:
- Eligibility for Systemic Therapies: Patients who were previously slated for localized treatments might now be considered candidates for systemic therapies, such as novel hormone therapies (like enzalutamide, as investigated in EMBARK) or chemotherapy, which are designed to target cancer cells throughout the body.
- Reevaluation of Treatment Strategies: The discovery of widespread disease may necessitate a complete reevaluation of the treatment plan. Instead of focusing solely on eradicating the primary tumor, the focus shifts to controlling or eliminating metastatic deposits.
- Potential for Curative Radiotherapy: In some cases, PSMA-PET can precisely pinpoint metastatic lesions, opening the door for targeted radiotherapy approaches, such as PSMA-targeted radioligand therapy. This approach uses radioactive molecules that bind to PSMA on cancer cells, delivering a lethal dose of radiation directly to the metastatic sites while sparing surrounding healthy tissues. This was not a viable option for patients who were not known to have metastases.
- Improved Clinical Trial Design: The study strongly advocates for the inclusion of PSMA-PET in patient selection for future clinical trials. This would ensure that trials accurately stratify patients based on their true disease burden, leading to more reliable and interpretable results. The current reliance on older imaging techniques in past trials, like EMBARK, means that the efficacy of certain treatments might have been underestimated or misapplied in some patient subgroups.
Dr. Jeremie Calais, senior author of the study, director of the Ahmanson Translational Theranostics Division’s clinical research program, and associate professor at the David Geffen School of Medicine at UCLA, emphasized the critical role of PSMA-PET: "Our study demonstrates the critical role of PSMA-PET in accurately staging prostate cancer, which can significantly impact treatment decisions and outcomes." This statement directly links the advanced imaging technology to tangible improvements in patient care.
A Shifting Landscape and Future Directions
The widespread adoption of PSMA-PET in clinical practice has already begun to change the landscape of prostate cancer imaging. However, as the UCLA study highlights, the integration of this advanced technology into standard care and its full impact on treatment efficacy are still being elucidated.
The researchers acknowledge that while their findings are compelling, further high-quality prospective data are needed to definitively prove the superiority of PSMA-PET for treatment guidance in terms of patient outcomes. "We have good rationales to assume that it is helpful to primarily rely on PSMA-PET findings," stated Dr. Holzgreve. "But more high-quality prospective data would be needed to claim superiority of PSMA-PET for treatment-guidance in terms of patient outcome. However, we are confident PSMA-PET will continue to advance prostate cancer staging and guide personalized therapies."
UCLA is actively pursuing this further research. Current efforts include:
- Analyzing Follow-up Data: The team is meticulously analyzing follow-up data from four UCLA trials to assess how PSMA-PET findings have influenced actual treatment decisions and, crucially, patient outcomes over time.
- International Collaboration: As part of a large international consortium involving over 6,000 patients, the UCLA team is investigating the prognostic value of PSMA-PET. This collaborative effort aims to build a robust understanding of how PSMA-PET findings correlate with disease progression and survival rates across a diverse patient population.
These ongoing studies are essential for solidifying the role of PSMA-PET in routine clinical practice and for developing evidence-based guidelines for its optimal use in prostate cancer management. The ultimate goal is to leverage this powerful imaging tool to achieve more personalized, effective, and potentially curative treatments for all prostate cancer patients.
Broader Impact and Considerations
The findings from the UCLA study resonate with a growing body of evidence supporting the superior sensitivity of PSMA-PET for detecting prostate cancer recurrence and metastasis. Previous studies, such as the observational study by Calais et al. published in The Lancet Oncology in 2021, which analyzed over 300 patients, also indicated a higher detection rate of metastatic disease with PSMA-PET compared to conventional imaging, particularly in patients with PSA levels between 0.2 and 0.5 ng/mL. However, the current study’s focus on a cohort specifically selected for high-risk nonmetastatic disease, intended for a trial like EMBARK, adds a crucial layer of evidence to the underestimation problem.
The implications extend beyond just identifying more metastases. It raises questions about the definition of "nonmetastatic" disease itself. If conventional imaging is consistently underestimating the spread of cancer, then treatment strategies based on that classification may be suboptimal. This could lead to a re-evaluation of the criteria used to enroll patients in clinical trials and the thresholds for initiating specific therapies.
Furthermore, the potential for PSMA-PET to identify candidates for PSMA-targeted radioligand therapy is a significant development. This form of treatment, which has shown promising results in clinical trials for metastatic castration-resistant prostate cancer, could potentially be offered earlier to patients with high-risk nonmetastatic disease if PSMA-PET accurately identifies small, treatable metastatic deposits.
However, the integration of new technologies into standard care is not without its challenges. Access to PSMA-PET imaging varies geographically and may be limited by insurance coverage and the availability of specialized radiopharmaceuticals and scanners. Continued advocacy and evidence generation are crucial to ensure equitable access to these advanced diagnostic tools.
In conclusion, the UCLA Health Jonsson Comprehensive Cancer Center study provides compelling evidence that conventional imaging may significantly underestimate the extent of disease in men with high-risk nonmetastatic hormone-sensitive prostate cancer. The widespread application of PSMA-PET imaging has the potential to revolutionize prostate cancer staging, leading to more accurate diagnoses, refined treatment strategies, and ultimately, improved outcomes for patients. The ongoing research at UCLA and around the world is vital to fully harness the power of this transformative technology and usher in a new era of personalized prostate cancer care.