Aug 29, 2023
By Jimmy O’Hara, Conquer Cancer
Prostate cancer is the second leading cause of cancer-related death among men in the U.S. and the fourth most diagnosed cancer worldwide.1 While the standard treatment—androgen deprivation therapy (ADT)—targets prostate cancer even in its advanced stages, most patients rapidly develop resistance to ADT and often experience side effects like fatigue, anemia, bone loss, and erectile dysfunction. The result of these adverse events is often a decreased quality of life and poorer survival outcomes.
It’s a reality that Conquer Cancer grant recipient Pedro Isaacsson Velho, MD, hopes to change. As an adjunct assistant professor at Johns Hopkins Hospital in Baltimore, MD, and a medical oncologist at the Moinhos de Vento Hospital in Porto Alegre, Brazil, Dr. Isaacsson Velho dedicates his research to bringing more tolerable and effective treatments to his patients, most of whom have limited options beyond standard care. He is working to uncover biological clues that flag whether patients’ tumors are resisting against or responding well to treatment.
“This area of cancer research must be accelerated due to prostate cancer’s heterogeneity, which can lead to resistance against certain treatments,” Dr. Isaacsson Velho said. “This makes it imperative to develop a range of therapies to combat various forms of the disease and overcome the resistance to androgen deprivation therapy.”
Finding New Biomarkers in Prostate Cancer
Emerging clinical studies point to DNA-related culprits that may cause immune systems to stubbornly resist standard care like ADT. Dr. Isaacsson Velho is building on this research to evaluate new treatment approaches, including some that are already proving effective in other areas of cancer care.
“Unfortunately, after some time, virtually all patients on ADT [experience disease progression] to a state called castration-resistant prostate cancer (CRPC), and survival ranges from 2 to 3 years,” he explained. “New effective treatments are needed to prolong survival and improve quality of life.”
Growing evidence indicates that certain tumors (those with DNA repair defects) show increased programmed cell death protein 1 (PD-1) pathway expression, Dr. Isaacsson Velho continued. These traits have proven to be predictive biomarkers for immunotherapy response in other cancer types. Recognizing this, Dr. Isaacsson Velho sought to investigate whether nivolumab, a checkpoint inhibitor, could potentially benefit a subset of patients with prostate cancer with DNA repair defects. “By targeting PD-1 pathways, nivolumab has shown efficacy in various cancer types,” he said, “and its use in prostate cancer with DNA repair defects warranted exploration.”
Supported by a Global Oncology Young Investigator Award (GO YIA) from Conquer Cancer, the ASCO Foundation, Dr. Isaacsson Velho launched a clinical study on the effectiveness of nivolumab for targeting metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects. The grant funding allowed him and his team to enroll 38 patients in the study, to implement genomic sequencing techniques, and to assess tissue samples for PD-L1 genetic expression. Leveraging this emerging immunotherapy and finding potential indicators of treatment response resulted in immense promise for future treatment strategies, along with improved patient outcomes.
“The key takeaway from my GO YIA research was the identification of potential biomarkers of response and resistance to immunotherapy in patients with prostate cancer with and without DNA repair defects, contributing to our understanding of the role of immunotherapy in this context,” Dr. Isaacsson Velho said. “GO YIA funding was pivotal in elevating the quality of our biomarker analyses within our study. This breakthrough finding has significant implications for treatment decision-making and the development of personalized approaches for patients with prostate cancer.”
Identifying these biomarkers can help oncologists to better select which patients will experience a favorable response to immunotherapy, ultimately improving prostate cancer outcomes and reducing exposure to ineffective treatments in certain patients. This is critical for patients with ADT-resistant disease.
“There is an unmet need for effective treatment options for patients with mCRPC that has developed resistance to standard therapies,” Dr. Isaacsson Velho said. “Exploring the potential of nivolumab in this specific patient population offered an opportunity to contribute to the advancement of personalized treatment approaches.”
A Promising Combination Therapy for Prostate Cancer
Insights gained from this initial work informed the next steps in Dr. Isaacsson Velho’s research—a subsequent clinical trial for patients with mCRPC—for which he received a Conquer Cancer Career Development Award (CDA). The ongoing trial is testing the effectiveness of bipolar androgen therapy (BAT), which involves testosterone dosages, paired with radium-223 (RAD), an intravenous injection. The funding enables Dr. Isaacsson Velho and his team to administer BAT-RAD on a monthly basis for six cycles.
Through the CDA-supported trial, which is currently accepting patients in the U.S. and Brazil, Dr. Isaacsson Velho and colleagues plan to evaluate the antitumor activity and patient tolerability of BAT-RAD combination therapy. His team is assessing overall survival and quality of life, as well as prostate-specific antigen (PSA), an indicator of recurrence. This research is particularly vital for patients with mCRPC, who generally have few treatment avenues.
“One of the key takeaways from the CDA research, which continues to significantly impact patients, is the improved understanding and efficacy of BAT-RAD” Dr. Isaacsson Velho said. “Thus far, our work has shown this combination therapy is safe and can be a potent tool in managing mCRPC, offering a promising new strategy to patients who have previously had limited options. Through this research, we are discovering the BAT-RAD approach not only slows down tumor growth, but also mitigates some of the side effects commonly associated with standard ADT and novel hormonal therapies. This has significant implications for quality of life, allowing patients to manage their disease with fewer adverse effects and leading to improved overall health outcomes.”
From the U.S. to Brazil: Patient Impact and Next Steps
Dr. Isaacsson Velho recalls a patient who underwent immunotherapy during his Conquer Cancer-funded research and who, at the start of the study, was very symptomatic. After a few months, the patient’s PSA levels were undetectable. Seeing such positive outcomes in his patients motivates Dr. Isaacsson Velho to continue advancing prostate cancer care.
“Four years later, my patient is still doing great, without any symptoms, and continues with an undetectable PSA,” he said. “Seeing this patient reach such a good outcome made me feel absolutely delighted and provided hope that these results could be extended to other patients. I am positive that the genomic findings of this study, including this patient’s outcome, may provide new insights to help more patients in the future.”
Since launching his CDA project, Dr. Isaacsson Velho has helped design and lead two more clinical trials in collaboration with multiple institutions between the U.S. and Brazil. One is a phase II pilot study to evaluate the usefulness of newly unveiled biomarkers in assessing patient responses to BAT. The other is a phase II investigation that measures the effectiveness of a novel BAT approach. Both trials are pending results and show promise for advancing prostate cancer research.
“Because of Conquer Cancer’s support, I am now able to advance my research to the next level,” Dr. Isaacsson Velho said. “I can broaden the scope of my investigations, collaborate with experts in the field, and translate my findings into clinical applications for patients.”
- Prostate Cancer: Statistics. Cancer.Net. Mar 2023. Available at: cancer.net/cancer-types/prostate-cancer/statistics.