Daniel Spratt, MD, discusses ongoing debate and uncertainties regarding the optimal use of treatment intensification in high-risk prostate cancer. 

Dr Spratt on Uncertainties Regarding Treatment Intensification in High-Risk Prostate Cancer

Daniel Spratt, MD, professor, Department of Radiation Oncology, School of Medicine, member, Developmental Therapeutics Program, Case Comprehensive Cancer Center, Case Western Reserve University, discusses ongoing debate and unanswered questions regarding the optimal use of intensified treatment approaches in high-risk prostate cancer.

The addition of abiraterone acetate (Zytiga) to androgen deprivation therapy (ADT) in patients with high-risk prostate cancer present with a lack of clear criterion for patient selection amidst the evolving landscape of diagnostic treatment modalities, Spratt begins. For example, the phase 2/3 STAMPEDE trial (NCT00268476) is often cited as evidence showing benefit with this approach; however, the patient population included in this study may not fully represent patients with high-risk localized prostate cancer who are seen in current clinical practice, Spratt explains.

In the STAMPEDE trial, patients without metastatic disease had exceptionally high prostate-specific antigen (PSA) levels, which may not reflect the current standard of care, especially with the advent of prostate-specific maturation agent (PSMA)–PET imaging, Spratt reports. Spratt notes that contemporary patients with similar PSA levels are more likely to have nodal or distant metastases. Consequently, there is uncertainty regarding which patients truly benefit from treatment intensification with abiraterone, he says.

Defining clear criteria for patient selection remains a challenge, Spratt continues. Although some institutions may adhere strictly to the criteria outlined in trials like STAMPEDE, others may adopt a more nuanced approach considering additional factors such as MRI findings and biomarkers like PSMA-PET, Spratt says. This variability in interpretation further complicates decision-making, he emphasizes.

Given the ongoing uncertainty emergence of alternative biomarkers and treatment strategies, caution should be employed when using abiraterone in this setting, Spratt states. Ongoing trials like the phase 3 ATLAS trial (NCT02531516) investigating apalutamide plus a GnRH agonist, and the phase 3 ENZARAD trial (NCT02446444) of enzalutamide (Xtandi) plus adjuvant ADT and radiotherapy, may provide valuable insights into the efficacy of different treatment approaches in high-risk localized prostate cancer, he notes. Until conclusive evidence is available, individualized decision-making based on patient characteristics and available data remains essential to optimize outcomes in this patient population, Spratt concludes.

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Daniel Spratt, MD, discusses ongoing debate and uncertainties regarding the optimal use of treatment intensification in high-risk prostate cancer.

Dr Spratt on Metastasis-Directed Therapy and Hypofractionation in Prostate Cancer 

Daniel Spratt, MD, professor, Department of Radiation Oncology, School of Medicine, member, Developmental Therapeutics Program, Case Comprehensive Cancer Center, Case Western Reserve University, highlights two significant shifts in prostate cancer: the integration of radiation therapy for metastatic sites and the trend toward hypofractionation in treatment sessions.

Regarding metastasis-directed therapy, technological advancements have enabled the treatment of multiple metastatic sites concurrently, Spratt begins. Historically, technical limitations have restricted the ability to address numerous lesions effectively; however, with modern technology, such as stereotactic body radiation therapy (SBRT), clinicians can now treat a higher number of metastases within shorter treatment courses. Ongoing trials are exploring the feasibility and efficacy of treating multiple metastatic sites, potentially revolutionizing the approach to metastasis-directed therapy, Spratt explains.

Additionally, there is a growing trend toward hypofractionation in radiation therapy, particularly in the management of localized prostate cancer and the post-operative setting, he continues. Clinical trials are investigating protocols involving lower numbers of treatment sessions, offering patients a more convenient and accessible treatment option. This reduction in treatment sessions not only improves patient convenience but also addresses potential barriers to treatment, particularly for patients who face logistical challenges or live at a distance from treatment centers, Spratt notes.

Furthermore, the adoption of hypofractionated regimens may enhance the acceptance of radiation therapy among referring providers and patients alike, Spratt says. The potential for reduced adverse effects associated with newer treatment modalities may help overcome historical biases and encourage greater utilization of radiation therapy as a primary or adjunctive treatment modality, he explains.

The integration of radiation therapy for metastatic sites and the adoption of hypofractionated treatment regimens represent significant advancements in radiation oncology practice, Spratt continues. These shifts hold promise for improving treatment outcomes, enhancing patient accessibility, and expanding the acceptance of radiation therapy as a viable therapeutic option across various clinical scenarios. Continued research and clinical trials will be essential to further refine and validate these evolving treatment approaches, Spratt concludes.

Daniel Spratt, MD, discusses the integration of metastasis-directed therapy and hypofractionation in prostate cancer.

Dr Spratt on the Use of Radiation in Low– and High-Risk Prostate Cancer

Daniel Spratt, MD, Vincent K. Smith Chair, Department of Radiation Oncology, The University Hospitals, Seidman Cancer Center, professor, chair, Radiation Oncology, Case Western Reserve University School of Medicine, discusses the use of radiation therapy in patients with low- and high-risk prostate cancer.

Oncologists typically categorize localized prostate cancer into National Comprehensive Cancer Network risk groups ranging from low-risk to high-risk, Spratt begins. The phase 3 ProtecT trial (NCT02044172), with long-term follow-up, compared active monitoring, akin to a less intensive form of active surveillance vs surgery vs radiation therapy, he states. Although this trial predominantly enrolled low-risk patients, approximately one-third of patients were intermediate risk, Spratt expresses. Given the trial's time frame, many low-risk patients would likely now be classified as intermediate risk by contemporary standards, he adds. Nonetheless, based on this evidence, active surveillance is generally preferred over radical therapy for low-risk prostate cancer cases, Spratt says.

For intermediate-risk patients, recent data indicate comparable tumor control outcomes between surgery and radiation therapy, he continues. Studies such as the randomized phase 3 PACE-A trial (NCT01584258) comparing surgery with stereotactic body radiation therapy (SBRT)—a type of radiation therapy involving just five treatments—consistently show higher rates of urinary incontinence and erectile dysfunction with surgery vs SBRT, Spratt elucidates. However, with advancements in radiation therapy, including image guidance and the use of rectal spacer gels in other trials, there's no significant disparity in moderate or bothersome rectal toxicity between surgery and radiation, contrary to outcomes with older radiation techniques, he emphasizes.

Therefore, in intermediate-risk disease, hypofractionated radiation, such as SBRT requiring fewer treatments, is now favored, he expands. In high-risk prostate cancer, the sole local therapy that has level 1 evidence demonstrating improved survival over hormone therapy alone is radiation therapy, often combined with long-term hormone therapy, Spratt adds. Furthermore, data from the phase 2/3 STAMPEDE trial (NCT00268476) indicates a benefit with the addition of abiraterone (Zytiga) to androgen deprivation therapy for highly select high-risk patients, he concludes.

Daniel Spratt, MD, discusses the use of radiation therapy in low- and high-risk prostate cancer.

Daniel Spratt, MD, professor, Department of Radiation Oncology, Case Western Reserve University School of Medicine; member, Developmental Therapeutics Program, Case Comprehensive Cancer Center, discusses research findings that have delineated the optimal sequencing of radiation therapy and hormone therapy for patients with prostate cancer.

Extending as far back as the 1970s, investigations have attempted to to discern the presence of a potential synergistic effect between radiation therapy and hormone therapy, such as androgen deprivation therapy, that inhibits androgen receptor (AR) signaling, Spratt says. Several clinical trials over the past few decades have aimed to define optimal strategies for the concurrent administration of radiation therapy and hormone therapy, Spratt explains.

Some of these trials were influenced by the notion that initiating hormone therapy prior to radiation therapy may mitigate adverse effects, such as hypoxia, or disease factors believed to contribute to radioresistance, Spratt notes. However, contemporary research challenges these hypotheses, indicating that administering hormone therapy prior to radiation therapy may not yield the anticipated oncologic advantages, Spratt emphasizes. Although hormone therapy can effectively target cancer cells, it may not be the optimal treatment strategy for enhancing the effects of radiotherapy, according to Spratt. Administering adjuvant hormone therapy immediately following radiation therapy may generate superior outcomes, Spratt says.

For instance, a preclinical study conducted by Spratt and colleagues explored the effects of sequencing AR signaling inhibitors (ARSIs) with radiotherapy neoadjuvantly, concurrently, or adjuvantly in prostate cancer cell lines. This study showed that delivering adjuvant ARSIs after radiotherapy was the most effective method for killing colony-forming cells and decreasing AR target gene translation and transcription in tumors.

Additionally, research has shown that radiation therapy can impede DNA damage repair, Spratt explains. Therefore, delivering radiation therapy alongside hormone therapy for an extended period may also be a strategy using these treatments that induces favorable synergistic effects, Spratt concludes.

Daniel Spratt, MD, discusses research findings that have delineated the optimal sequencing of radiation therapy and hormone therapy for patients with prostate cancer.

Dr Spratt on Sequencing Radiation Therapy and Hormone Therapy in Prostate Cancer

Daniel Eidelberg Spratt, MD, assistant professor, radiation oncology, University of Michigan Health System, discusses the combination of immunotherapy and radiation in patients with prostate cancer.

Immunotherapy in patients who have metastatic disease of different types of cancer, have shown great response rates. There are ongoing trials that are focused on combining radiation and immunotherapy to try to release antigens so the immunotherapy knows the cancer should not exist, Spratt explains.

Prostate cancer has had less success than different tumor types, such as multiple myeloma. Some of the initial trials being done have not shown favorable results but the trials are still ongoing, Spratt states.

Dr. Spratt on Combination of Immunotherapy and Radiation in Prostate Cancer

Daniel Eidelberg Spratt, MD, assistant professor, radiation oncology, University of Michigan Health System,  discusses genetic testing in prostate cancer.

It is a very exciting time in prostate caner, says Spratt. It is now possible to use biopsies or radical prostatectomy specimens to do genetic tests. There are a variety of tests that are commercially available for use in prostate cancer. As more and more patients undergo these genetic-based tests, we will gain a better understanding of patient’s risk of recurrence or death from the disease, says Spratt.  

We are already in an era where more and more patients are going to get genetically tested, he says. In other cancers, including breast cancer there are already tests that helps predict risk or recurrence and response to chemotherapy. If these types of tests could be adapted in prostate cancer it is really going to help personalized treatment for all men with the disease, says Spratt.

Dr. Spratt on Growing Role for Genetic Testing in Prostate Cancer

Daniel Eidelberg Spratt, MD, assistant professor, radiation oncology, University of Michigan Health System, discusses challenges regarding the classification of risk groups in prostate cancer.

Many risk factors that are used to help determine treatment for prostate cancer are made up of relatively insensitive tests, says Spratt, including the rectal exam, PSA, or Gleason score.

These tests are not fully arcuate because they don’t provide any information regarding genetic risk factors.  Oncologists must look at phenotypes, or the way all these features group together, to guide treatment, rather than actually genetically understanding how aggressive the tumors are or how responsive they may be to therapies.

​Daniel Eidelberg Spratt, MD, assistant professor, radiation oncology, University of Michigan Health System, discusses challenges regarding the classification of risk groups in prostate cancer.

Daniel Eidelberg Spratt, MD

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