PCF hosts an Annual Scientific Retreat to share the latest research findings, inspire collaboration, promote mentorship, and honor the newest awardees. Meeting sessions at the 30th Retreat addressed basic biology and genetics research, clinical trials, treatment resistance, and the future of AI in prostate cancer.
Below are just a few examples of cutting-edge findings presented at the meeting.
- A clinical trial suggests synergistic effects in combining treatments for advanced prostate cancer
- A new test identifies deadly neuroendocrine prostate cancer, and may also be useful in lung cancer
- AI has the potential to improve prostate cancer diagnosis and characterization
- A large study of men of African ancestry reveals a complex and varied genetic profile
Encouraging results for combination treatment with LuPSMA + enzalutamide in advanced prostate cancer
Louise Emmett, MD
St Vincent’s Hospital Sydney, Australia
Enzalutamide is an androgen receptor (AR)-targeted therapy that is approved for several indications in advanced prostate cancer. However, the disease does not always respond to enzalutamide, and additional treatment approaches are urgently needed.
LuPSMA (177-Lutetium-PSMA-617; Pluvicto®) was FDA-approved in 2022 for certain patients with metastatic castration resistant prostate cancer (mCRPC). This therapy delivers “liquid radiation” to kill prostate cancer cells that have the PSMA protein on their surface. The Phase 2 ENZA-P trial, led by PCF-funded investigator Dr. Louise Emmett, is testing enzalutamide alone vs. enzalutamide + LuPSMA in patients with mCRPC who have not previously received chemotherapy for mCRPC, and who have cancer visible on a PSMA PET scan.
Of note, the dosing of LuPSMA is “adaptive,” meaning that patients receiving LuPSMA undergo a PSMA PET scan at baseline. After the first 2 doses of LuPSMA, patients undergo another PSMA PET scan; only patients whose tumors remain PSMA PET-positive receive another 2 doses of LuPSMA. This approach may help to reduce toxicity by avoiding treatment of patients who are unlikely to benefit from additional doses.
At the time of Dr. Emmett’s presentation, data on PSA progression free survival (PSA PFS; i.e., time from enrollment until PSA levels rise) was available for 117 patients. These early results were promising: patients who received LuPSMA + enzalutamide had a longer average time to rising PSA (13 months) vs. patients who received enzalutamide alone (approximately 8 months). Additionally, 93% of patients who received LuPSMA + enzalutamide saw their PSA levels drop by 50% or more compared with 68% of patients who received enzalutamide alone. The frequency of side events was similar between the two groups.
This is the first trial to use “adaptive dosing” of LuPSMA based on an interim PSMA PET scan. Overall, it provides strong evidence that combining LuPSMA with enzalutamide delays disease progression in patients with mCRPC. The trial is ongoing, with planned follow-up of progression-free survival and overall survival in 2024.
Finding NEMO: New Methods to Identify and Target Neuroendocrine Prostate Cancer
Himisha Beltran, MD
Dana-Farber Cancer Institute
Neuroendocrine prostate cancer (NEPC) is an advanced, aggressive form of castration-resistant prostate cancer (CRPC). New approaches to understanding and treating this life-threatening form of the disease are a priority area of research for PCF.
You may have learned in school about DNA (genes), the molecular instructions that tell cells how to grow and operate. On top of genes is an additional mechanism called “epigenetics” that controls which genes are active, and when. This allows for the body to have many different types of cells, despite all sharing the same set of genes. However, cancer also uses epigenetics to cause cells to grow out-of-control and to change their behavior.
Dr. Himisha Beltran is a leader in this field, having received multiple PCF awards. She presented her team’s work on a specific epigenetic change called DNA methylation. This simply means that the behavior of a gene is changed by the attachment of a molecule called a “methyl group.” DNA methylation patterns can be used to distinguish NEPC from typical CRPC (adenocarcinoma) by looking at cells in the tumor as well as DNA shed from the cancer into the blood. Her team has developed a test called NEMO (NEuroendocrine MOnitoring) to determine the total amount of tumor and the extent of NEPC vs. prostate adenocarcinoma in patients, based on DNA methylation patterns. The test is noninvasive and uses a blood sample, minimizing discomfort in patients who have likely already endured many procedures.
How well does this test work? The team evaluated NEMO in a clinical trial using samples from patients with NEPC and patients with typical CRPC. Overall, NEMO has demonstrated 93-97% accuracy in identifying patients with NEPC, based on data from more than 150 patients.
The NEMO test was also able to identify patients with small cell lung cancer, another type of cancer with neuroendocrine features. Dr. Beltran and team are continuing their work to identify when and how often NEPC develops, how DNA methylation may impact response to treatment, and new targets to help defeat NEPC.
Optimizing AI in Diagnosis and Characterization of Prostate Cancer
Tamara Lotan, MD
Johns Hopkins University
Currently, pathologists use Gleason score/Grade Group to describe the features of prostate cancer as seen under a microscope, providing information about the aggressiveness of a patient’s disease. However, there is room for improvement to give patients and their doctors a more accurate view of their likely course and outcome.
Several algorithms using AI or “deep learning” have been developed to diagnose and grade prostate cancer using pathology slide images. Dr. Lotan is developing a new deep learning tumor identification and grading algorithm called AIRAProstate. Testing of this algorithm on prostate slide images demonstrated 92-98% accuracy in detecting the presence of cancer and 93-96% accuracy for determining the tumors’ Grade Group. The AIRAProstate algorithm also outperformed 5 other top-ranked public AI algorithms.
It is now being tested in the setting of Active Surveillance to predict which patients may be reclassified with more (or less) aggressive cancers, which could impact decisions about if and when to begin treatment. AIRAProstate is also being tested on its ability to predict biochemical recurrence or risk of metastasis after radical prostatectomy.
Importantly, the team is including a cohort comprised of ~50% Black patients in this work, to ensure that the algorithm will perform optimally in underrepresented minority populations.
African-Specific Molecular Taxonomy of Prostate Cancer
Vanessa Hayes, PhD
The University of Sydney, Australia
In the U.S., Black men are about 70% more likely to be diagnosed with prostate cancer and about twice as likely to die from it. The reasons are complex, including environmental factors, access to medical care, systemic racism, and genetics. Less is known about genetics and prostate cancer disparities among men in Africa compared to men of European ancestry.
Studies have found that prostate cancer mortality rates are 2.5-fold higher in Sub-Saharan Africa compared to the U.S. Patients in South Africa have a 2.1-fold greater risk of presenting with a high-grade prostate cancer compared to African American patients and have significantly higher PSA levels at diagnosis.
Over 1.5 billion people live in Africa today. However, only 2% of all sequenced genomes (i.e, full sets of genes) come from people of African ancestry. The largest prostate cancer genome sequencing resource currently contains no genomes from patients on the African continent.
Dr. Hayes and colleagues sequenced the whole genomes of 183 prostate cancers from patients in Africa, Brazil and Australia. They found several important differences between African ancestry patients and European-Australian ancestry patients. For example, African ancestry patients had over ~1 million more variations in their genomes than European-Australian ancestry patients. Interestingly, a small number of White South African patients also had features in their tumors specific to African patients. This suggests there may be an environmental carcinogen that is contributing, at least in part, to aggressive prostate cancer in Southern African patients. The role of ancestral vs. geographical/environmental effects is being studied.
Ultimately, it is crucial to study prostate cancer in diverse populations to understand how well existing treatments work (or don’t work) and to identify gaps where new drug targets and strategies are needed.