Individual patient characteristics and tumor factors should affect treatment choice and regimen for prostate cancer. Personalizing prostate cancer treatment was a topic of discussion at the 2024 Society of Nuclear Medicine & Molecular Imaging (SNMMI) Annual Meeting.

Following these proceedings, featured expert Oliver Sartor, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Sartor’s clinical perspectives on these findings are presented here.

As discussed in a prostate-specific membrane antigen (PSMA) radioligand therapy tumor board session at the 2024 SNMMI Annual Meeting, personalization is really key in prostate cancer because the disease history is so variable from individual to individual. Even at the very beginning when somebody is first diagnosed with prostate cancer and everything from active surveillance to radical prostatectomy are considerations, there is no one-size-fits-all approach.

We try to risk stratify patients into higher- or lower-risk categories and then match their age and comorbidities to this to create a treatment strategy that is based on them. And I will be the first to say that a 46-year-old marathon runner and a 98-year-old person residing in a nursing home are not the same, and that is obvious. But there are also so many differences between, for example, a Gleason 6 and a Gleason 10, as well as between localized, oligometastatic, and frank metastatic disease. Personalization starts at the beginning, and then it carries through the course of treatment.

There is some commonality related to the treatment of those patients who are advancing with aggressive disease, where hormonal therapy is really the mainstay of what we do. We have older hormones, we have newer hormones, we have hormones plus therapies such as chemotherapy, and we have a variety of ways to approach treatment. If you are treating advanced disease, we typically initially think about some type of hormonal therapy followed by some type of intensification if there is a need for that patient to have more aggressive therapy, and then there is a potential discussion about the need for chemotherapy.

Unfortunately, patients who have advanced metastatic disease are inevitably going to progress, whether or not we are using ADTs and newer hormones such as darolutamide, abiraterone, enzalutamide, or apalutamide, plus or minus chemotherapy. Metastatic castration-sensitive prostate cancer is, unfortunately, not going to be the type of disease that we can plan on curing. Now, we might pick out a few oligomets that do fairly well, but if the patient has frank multifocal metastatic disease, then there is a problem, and these patients will not be cured.

After patients fail their initial therapy, there are various personalization strategies that can be used, depending on the prior treatments, and I will review a couple of them here. PARP inhibitors are used specifically for those with certain DNA repair mutations, and the poster child here is BRCA2 mutations. So, if a patient has been through initial hormonal therapy, say with ADT—and particularly if they have a BRCA mutation—then something like abiraterone plus olaparib may be a great choice, or maybe enzalutamide plus talazoparib. If they have already failed an ARPI, then they might receive PARP inhibitor monotherapy. Again, BRCA2 mutations are the poster child for success. There are other mutations where PARP inhibitors are potentially active, such as PALB2 mutations, but that gets a little more complex.

There are rare subsets of patients who are really immunotherapy responsive, and these are patients who are microsatellite instability high, have mismatch repair mutations, and are tumor mutational burden high, and there is a small subset who may respond quite well to PD-1 inhibitors such as pembrolizumab, which is US Food and Drug Administration (FDA) approved. And then there are radionuclides. In terms of selectivity, we look at the PSMA positron emission tomography (PET) expression and think about using PSMA-targeted therapy with something such as ¹⁷⁷Lu-PSMA-617. Currently, this class of therapy is restricted to those who have previously had chemotherapy and one of the advanced hormones, such as abiraterone or enzalutamide, and progressed. This is based on the VISION trial. There are also patients who are potentially treatable with radium-223 who have bone-dominant metastatic disease. Finally, there are aggressive variants, for which we might think about adding chemotherapy regimens containing carboplatin.

There are many different approaches to patients, particularly those with oligometastatic disease. Number one, you have the opportunity just to leave things alone, you do not need to treat everything you see. The natural history is not always terrible for these patients. And there is an interesting trial at the National Cancer Institute (NCI) is being run by Ravi A. Madan, MD, in which PSMA PET–positive lesions are being monitored to see what happens over time, because the truth is, we do not know. We do not really have a natural history study. So, that is one end of the extreme: to see it and monitor it but not treat it. Among those in whom it is feasible, we very commonly may introduce a stereotactic body radiotherapy (SBRT) option.

You can use SBRT alone and see what happens. Now, if a patient has a little more disease or a more aggressive course, is perhaps slightly younger, or has lesions that are more distant, you may want to consider SBRT in combination with hormonal therapy. However, there is a lot of debate over what type and the length of hormonal therapy. We do not have good comparative studies regarding the type and duration of hormone therapy, so what we do in our practice is plan on an intermittent approach. We might treat for 6 months, give SBRT plus 6 months of an ADT (often with abiraterone), and then monitor to determine what happens thereafter. For those patients with polymetastatic disease, which is not really susceptible to SBRT, we probably need to treat with hormonal therapy and do not really have a local option.

Something that I think is important is a clinical trial that is activating across the globe right now. It is already active in Canada and Israel, and it will be coming to the United States soon. And in this trial, we are looking at patients with oligometastatic disease, 1 to 5 lesions, and a prostate-specific antigen doubling time of less than 10 months. All patients will receive SBRT, and then half of the patients will be randomized to receive ¹⁷⁷Lu-PSMA-617, and they will have a metastasis-free survival end point. So, we are going to avoid hormones but give systemic therapy with ¹⁷⁷Lu-PSMA-617 and in combination with SBRT, which many consider to be the standard of care. That is an interesting approach as well.