Prostate cancer will affect the lives of 1 in 8 men, often occurring later in life when patients are dealing with other challenging health conditions, such as arthritis or chronic obstructive pulmonary disorder. As patients tend to be older and sicker, there’s a need to find effective treatments with milder side effects that don’t affect the patients’ quality of life.
Stanford Cancer Institute member Sandy Srinivas, MD, is a medical oncologist who leads the Stanford Cancer Institute clinical research group for genitourinary cancer and the clinical urologic group. This collaborative team is dedicated to finding more tolerable treatments that can fight the disease when it’s at its worst, so patients can live their golden years at their best.
Srinivas says, “Our team includes urologists, radiation oncologists, nuclear medicine scientists, and basic scientists. I’m proud to be part of this multidisciplinary team caring for prostate cancer patients.”
The unmet needs of prostate cancer
Prostate cancer feeds on androgen hormones, with the main one being testosterone. While localized prostate cancer is treated with surgery or radiation therapy, advanced disease and recurrences are targeted with androgen-deprivation therapy to lower testosterone or make it unavailable to tumor cells.
Srinivas mainly treats patients with advanced disease whose treatments are aimed at reducing testosterone. She says that most patients have an initial response to androgen-deprivation therapy, but tumor cells can develop resistance. This results in castrate-resistant cancer, a lethal type of prostate cancer that continues to grow even when testosterone is low, with the median survival being about two years after diagnosis.
She says, “Many of the drugs that we have had in the past, including hormonal drugs, have all been moved to earlier lines of therapy, so when patients develop castrate resistance, we are left with very few options.”
Because patients tend to be older with multiple comorbidities, it’s challenging to find treatments that are effective, well-tolerated, and don’t negatively impact quality of life, such as exacerbating fatigue, dizziness, or cognitive decline. This challenge is present at all stages of prostate cancer, including cancers that have yet to develop castrate resistance.
Srinivas says, “The big challenges in this disease, and the unmet needs, are really finding effective therapies that can help people live longer with a better quality of life and eventually have therapies that may even allow us to eradicate this disease.”
Leveraging PSMA for better diagnosis and targeted therapies
Prostate-specific membrane antigen (PSMA) is a protein that is highly expressed on patients’ tumors, making it a target for innovative strategies to diagnose and treat prostate cancer.
A recent breakthrough is PSMA-based Positron Emission Tomography (PET) imaging. This scan uses targeted radiation to locate PSMA and identify where prostate cancer cells are in a patient’s body. Srinivas says it has revolutionized the way prostate cancer patients are imaged, especially for earlier disease stages.
“It is extensively used in staging patients with localized disease and for patients with a biochemical recurrence after having had local therapy.”
Theranostics has changed how we treat patients with more advanced disease. We now have therapeutics specific for those with widespread metastatic disease identified by PSMA imaging."
PSMA-based PET imaging also plays a crucial role in radioligand therapy, which consists of a molecule that binds to a target on the surface of cancer cells and a radioactive isotope that goes into the cancer cell to destroy it from the inside. Pluvicto, a groundbreaking radioligand therapy for prostate cancer, relies on PSMA-based PET imaging for precision targeting. Once imaging locates the cancer cells, Pluvicto binds to PSMA and directly delivers the radioactive isotope Lutetium-177 into the cells. This combination of diagnostics and treatment is called theranostics.
Srinivas says, “Theranostics has changed how we treat patients with more advanced disease. We now have therapeutics specific for those with widespread metastatic disease identified by PSMA imaging.”
Pluvicto was FDA-approved in 2022 to treat patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who had previously undergone androgen-deprivation therapy and chemotherapy. In 2025, the FDA approval was expanded to an earlier line of treatment for PSMA-positive mCRPC patients who could delay chemotherapy. Srinivas notes that Stanford participated in the clinical trials that led to FDA approval and currently uses Pluvicto in their clinics. She says the drug has been effective for many patients, especially older patients whose overall health status does not make them great candidates for chemotherapy. Unlike chemotherapy, Pluvicto is well-tolerated with few side effects.
The drug is administered every six weeks, and providers can identify early on who will benefit based on a blood test for prostate-specific antigen (PSA), a marker used to evaluate prostate function. After the first or second treatment cycle, patients who benefit have a drop in their PSA levels of 50% or more. Srinivas says that Stanford is fortunate to have nuclear medicine scientists who can perform a type of 3D imaging called SPECT that visualizes blood flow and cellular activity to determine if the patient is benefiting from the drug immediately after treatment, and if not, prevent the patient from undergoing more cycles of ineffective therapy.
Stanford recently completed a trial to see if newly diagnosed metastatic prostate cancer patients would benefit from earlier Pluvicto treatment, and Srinivas says the results are promising. Stanford is also participating in ongoing clinical trials to see if some patients would benefit from more or fewer treatment cycles. These trials are being conducted by nuclear medicine scientists in collaboration with medical oncology.
Even though Pluvicto is a breakthrough treatment, only 50% of patients benefit from the drug. Her group is working with basic scientists and clinicians to compare patient samples collected at baseline and after three cycles. They aim to examine RNA signatures that may identify markers in patients who benefit and those who do not, in order to understand the mechanisms of resistance preventing the drug from being effective in all patients.
Ongoing research into promising treatments and diagnostics
Having identified PSMA as a target, Srinivas is excited about other therapeutic areas, including immunotherapy. Prostate cancer is considered to be a cold tumor, meaning it does not elicit a strong immune response and renders immunotherapy ineffective. However, researchers are beginning to see benefit from bispecific antibodies, which attach to PSMA on cancer cells and to the CD3 antigen on a patient’s T cells to direct T cells to kill the cancer.
Srinivas says, “We have gone through the first few generations of these drugs, and now we are at the point where we are seeing benefit. These studies are moving on to phase 3 trials. I’m really excited that immunotherapy is what is going to give our patients the durable response seen in other types of cancer, and I’m hoping that will be applicable to our patients with prostate cancer soon.”
Srinivas notes there is a growing interest in studying alternative agents for PSMA-negative patients. She cites an ongoing trial evaluating copper 64 as a diagnostic agent that could be helpful for patients who do not express PSMA on their tumor cells. She says the trial is a strong collaboration involving nuclear medicine researchers, urologists, and radiation oncologists, and the group is dedicated to identifying new targets that could improve diagnosis for patients with localized disease. Stanford is also looking at agents that target the gastrin receptor growth factor, which is highly expressed on prostate cancer cells. One such agent, bombesin, can detect the growth factor and be used in radioligand therapy. Additionally, antibody drug conjugates, which deliver chemotherapy agents straight to cancer cells and spare healthy cells, now have a few clinical trials in prostate cancer.
Stanford researchers are also looking at different radioactive isotopes for radioligand therapy. Srinivas explains that Pluvicto is a beta-emitting isotope, and researchers are interested in looking at alpha-emitting isotopes, which are more targeted and may have fewer side effects. Currently, they are looking at the alpha-emitting particle actinium 225 in patients with metastatic castrate-resistant prostate cancer. There is interest in combining the two different isotopes to see if patients have a more durable benefit, help overcome resistance, and if moving it to earlier lines of treatment, even before Pluvicto, would make sense.
“I’m really excited and hopeful that in the years to come, there’s going to be many more options for our patients with advanced disease and not just limited to chemotherapy. Stanford is really good at approaching this cancer from a multidisciplinary point of view. I'm really proud of the engagement of our clinicians, urologists, radiation oncologists, and now our nuclear medicine colleagues, as well as our pathologists and our radiologists, all contributing to making improvements in moving this field forward.”