Trends in Managing Advanced and Metastatic Prostate Cancer

Prostate cancer is the third most common cancer overall, and the most common in men, within the US. Great clinical gains have been made in the management of advanced prostate cancer, but metastatic prostate cancer remains incurable and carries significant morbidities in its clinical symptomatology and the side effects of managing the disease.

As clinicians pursue further advances in the management of prostate cancer, the fusion of multimodal therapy continues to gain traction. Catherine H. Marshall, MD, MPH, an assistant professor of oncology at the Johns Hopkins University School of Medicine, was recently interviewed by Daniel Tennenbaum, MD to help clarify the recent trends in management of advanced and metastatic prostate cancer. More specifically, she discussed when, as a medical oncologist, she utilizes radiation therapy in the management of advanced prostate cancer.

Dr. Tennenbaum: Today, we’re going to talk about how and when you, as a medical oncologist, incorporate radiation into the management of men with metastatic prostate cancer. As a point of introduction, when do medical oncologists typically get involved in the management of prostate cancer? As a urology resident, I can’t help but think that for localized disease, it’s either the urologist or the radiation oncologist who is usually “at the front lines,” and that the medical oncologist will come in to provide adjuvant therapy or treatment of advanced or metastatic disease. Is that something you would agree with?

Dr. Marshall: Yes, that’s definitely something that I would agree with. Obviously, most prostate cancer, when it gets diagnosed in this country, is diagnosed when it’s still local. Usually, medical oncologists do not see those patients. There are some patients with very high-risk prostate cancer who are getting androgen deprivation therapy (ADT) and abiraterone, so some of those patients, I see for the administration of their systemic therapy. For the most part, the patients I see are men who have metastatic disease, or who have disease recurrence after localized treatment, which we refer to as biochemical recurrent disease.

And when you say ‘metastatic disease’, obviously not all metastatic prostate cancer is created equally. Can you please elaborate on hormone-sensitive versus hormone-refractory metastatic prostate cancer, as well as the concept of metastatic versus nonmetastatic hormone-refractory disease?

There are probably 3 categories I would say. (1) non metastatic, meaning disease is not visible on scans. Traditionally, we use conventional CT and NM bone scans to define this but can use PSMA PET/CT too; (2) oligometastatic disease, meaning that there is some disease that is visible but there are only a few areas of disease; (3) metastatic disease, meaning it is apparent on scans. Again, traditionally, we use CT and NM bone scan to define this.

Regarding whether the disease is considered hormone sensitive or hormone refractory, it is just relative to whether or not the patient has been treated with androgen deprivation therapy. Usually, at initial cancer diagnosis, when a patient has not been exposed, nor has the cancer been exposed to any androgen deprivation therapy, we consider that to be hormone naive. If the disease progresses despite having castrate levels of testosterone, then that’s when we consider the disease to be hormone refractory, meaning that it’s growing despite the castration levels of testosterone.

At what point do you start to consider incorporating radiation therapy (RT) into the treatment of your metastatic patients? Is RT something you would use up front for local control? Are you using it for adjuvant therapy?

For patients who present with de novo metastatic disease, where their first presentation of prostate cancer is metastatic, and if they have significant lower urinary tract symptoms, then sometimes I’ll refer these men for radiation just because of the therapeutic and symptomatic benefit. Additionally, for patients who have low-volume metastatic disease, there’s benefit to considering radiation to the prostate for those patients in conjunction with systemic therapy.

On the other hand, for the patients who have recurrence of their disease after local treatment, there may still be a role for salvage radiation. This is when there’s a biochemical recurrence and the radiation gets delivered to the postprostatectomy prostatic bed, and sometimes pelvic lymph nodes.

With PSMA imaging, or even conventional imaging, we are now sometimes identifying oligometastatic disease that may be amenable to radiation. If patients have recurrent disease, and we identify oligometastatic disease, then sometimes I will refer those patients to radiation oncology to see about getting radiation to the sites of oligometastatic disease.

What about for patients who don’t have oligometastatic disease but rather have symptomatic metastatic disease? Bone lesions are the obvious circumstance to consider, of course. Is SABR an option for symptomatic metastatic disease?

Yes, it absolutely is. Sometimes, those patients will get conventional radiation, external-beam radiation therapy (EBRT) or SBRT, but radiation is definitely used in the palliation of symptoms. Though this usually doesn’t come up in hormone-sensitive disease, it certainly can. We do see that in more advanced disease of course.

Got it. With all that being said, what kind of benefit are we seeing with the use of radiation in patients who have already been diagnosed with metastatic disease?

The benefits really depend on the different contexts. In treatment to the primary tumor for low-volume metastatic disease, subset analysis of the STAMPEDE trial showed an overall survival benefit. In the other studies we’ve spoken about, you’re really looking at the progression-free survival as the largest benefit to the patient, trying to delay the time to initiation of hormone therapy. That’s usually what I talk to my patients about, extending time to disease progression.

Moving back to what you were mentioning earlier, using EBRT for low-volume local control. In our discussion prior to this interview, you mentioned the Journal of Clinical Oncology article by Rusthoven et al, “Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer.” One aspect of that article I found interesting was its suggestion that cytoreduction of some form may have clinical benefit in the metastatic prostate cancer setting. From my previous understanding, that’s a somewhat controversial position.

Yes. The HORRAD trial was an older study which did not show a benefit. However, patient selection is key. In the STAMPEDE study, subset analysis showed benefit in patients with low volume metastatic disease. A meta-analysis of the two trials for men with low-volume disease showed benefit. So for patients with low-volume metastatic disease, I usually refer to radiation oncology for a discussion about adding in radiation.

We’ve seen in the last number of years a step toward bringing therapies that were offered later in disease courses earlier and earlier, particularly for prostate cancer. Do you foresee a future where conjunctive systemic therapy and radiation are offered even in just localized disease?

Yes, and some of that is already happening now. With very high-risk prostate cancer, abiraterone is now being used in that setting, too. It started out with radiation, and then radiation and ADT, and now radiation, ADT, and abiraterone for a short period of time, and then stopping all those therapies. In oligometastatic disease, initially we would not use both hormone therapy and radiation, and now we have trials combining SBRT plus with other therapies as well. The ultimate goal is to figure out what the best treatment is for each individual patient, and we obviously still have a way to go toward figuring that out. Who really needs more intensification of treatment versus maybe de-escalation of treatment for others?

When you mention individualizing patient care, are there any subsets of patients—whether it be by age, family history, or race—that are responsive to radiation therapy when you’re already putting them on systemic therapy?

Well, I think we will find that there probably are some subsets of prostate cancer, again, probably related to more aggressive disease, where there’s going to be more micrometastatic disease that you’re not targeting. The patients who are more likely to have that are probably going to be the ones who are less likely to benefit from this localized approach.

Lastly, I like to ask everyone we interview this question: What does the future hold for the management of men with metastatic prostate cancer?

I think the future of managing metastatic prostate cancer is going to be dramatically different in the next 20 years. Recent trials have helped us realize that there are definitely some patients who need an escalation of therapy and more therapy up front, and I think the reverse will be true, too. We will find that some patients can afford a de-escalation of therapy and less therapy. I think, as we will continue to identify new targets and new therapies, that will be successful against those targets.

Will there be any further implementation of immunotherapy in prostate cancer?

I think so. I definitely think so. Whether, again, that will be new targets or different combinations, I think we will figure out immunotherapy in prostate cancer.

Daniel Tennenbaum is a urology resident at Maimonides Medical Center in Brooklyn, NY. His interests include surgical education and GU oncology with a focus on pediatric malignancies.

References

1. Deek MP, Van der Eecken K, Sutera P, et al. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials. J Clin Oncol. 2022;40(29):3377-3382. doi:10.1200/JCO.22.00644

2. Burdett S, Boevé LM, Ingleby FC, et al. Prostate Radiotherapy for Metastatic Hormone-sensitive Prostate Cancer: A STOPCAP Systematic Review and Meta-analysis. Eur Urol. 2019;76(1):115-124. doi:10.1016/j.eururo.2019.02.003