Metastasis-directed RT plus hormone therapy shows benefit in oligometastatic prostate cancer

In a recent interview, Chad Tang, MD, discussed the background and implications of findings from the EXTEND trial, which explored the addition of metastasis-directed therapy (MTD) to intermittent hormone therapy for patients with oligometastatic prostate cancer.¹

"I think there may be some interest in the future potentially utilizing, not only metastasis-directed therapy, but also an intermittent hormone therapy regime, as these men can often be years without hormone therapy," said Chad Tang, MD.

Overall, EXTEND is an ongoing, randomized, phase 2 basket study (NCT03599765) enrolling patients with solid tumors who were given hormone therapy either with or without local therapy. Specifically in the prostate cancer cohort, 87 patients were evenly randomized to radiation plus intermittent hormone therapy or hormone therapy alone. Results for the prostate cohort showed that patients receiving the combination of MDT and intermittent hormone therapy had improvements in progression-free survival (PFS) and eugonadal PFS.

Tang, is an associate professor of radiation oncology at The University of Texas MD Anderson Cancer Center.

What treatment options are currently available in the prostate cancer space?

Tang: For metastatic castrate sensitive prostate cancer, for systemic therapy, the most common regime is some sort of continuous hormone regime. Most likely, this is regeneration anti-androgens, such as apalutamide [Erleada], enzalutamide [Xtandi], darolutamide [Nubeqa], or abiraterone acetate [Zytiga] as a cemetery backbone. As a growing indication of its use, if you have many metastatic sites, radiation could also be an option to control those sites as well. For oligometastatic prostate cancer, there is a growing trend to do radiation therapy, in addition to potentially systemic therapy.

What have been some recent updates in this space?

There have been 2 randomized trials for oligometastatic prostate cancer, called STOMP [NCT01558427] and ORIOLE [NCT02680587]. They randomized patients to radiation in metastatic patients vs observation. What they showed was that radiation delayed the PSA progression that inevitably occurs in these patients when they were just observed. We know the radiation does, by itself, delay the progression. We also know from other trials that radiation therapy can combine synergistically with hormone therapy and from earlier trials, that upfront hormonal therapy for metastatic disease can result in OS benefit vs delaying hormone therapy.

Can you discuss the EXTEND trial? What were the methods and design of the study?

EXTEND is a basket study, which means we're looking at multiple histologies where each basket is powered by itself to look at a specific question. In this EXTEND hormone basket, patients with oligometastatic prostate cancer chosen to be an intermittent hormone therapy, were randomized to radiation therapy, could be surgery, but it's all radiation therapy, vs not. Then the hormone therapy was stopped 6 months later. You get a minimum of 8 months, because you needed 2 months of hormones before. This mirrors an intermittent hormone regime. Patients are then monitored, and then when their PSA rises, we call it progression when they speak certain thresholds, we put the patient's back on hormone therapy.

The primary end point was progression-free survival, which could be from PSA or from your graphical assessment. Secondarily, we're trying to see how long patients can be off the hormones and have a normal testosterone because all men were on hormone therapy, they hate it. They want their testosterone back, and it's a big quality of life impact for them.

One thing is that this is part of a larger basket study. We're randomizing 300-400 patients on it. We're going to ask questions that are individual to each basket. We will also be asking universal questions such as, where did metastases come from and what are the effects of radiation across histologies to the immune system? So, we'll try to look into that across insolvencies and there is more to come.

What were the findings? How did this impact adding metastases directed radiation therapy plus hormone therapy in this patient population?

The primary end point was that we have significant improvement in PFS, which directly translated to an improvement and reduction in hormone therapy exposure. Secondarily, we did see our main, most important secondary end point which is time when a patient hits their normal level of testosterone. Then we saw that progression was also improved.

What do these findings mean regarding future directions of research in this space?

I think there may be some interest in the future potentially utilizing, not only metastasis-directed therapy, but also an intermittent hormone therapy regime, as these men can often be years without hormone therapy. It can convert universally lethal disease when you compare these 2 modalities in select patients with chronic disease. Not only that, but there are substantial amounts of time with a chronic disease when you get to recover your testosterone and all men benefit from that because. Not only does it prevent all these adverse events, such as hot flashes, night sweats, loss of libido, it also causes increased incidence of cardiovascular risk of stroke, obese, adiposity, etc. I think it's a big win for patients if we can develop these chronic strategies that not only treat the disease with extra control, but also maintain a quality of life.

What unmet needs still exist in the space?

I think the biggest unmet need is how we think about oligometastatic prostate cancer. In my opinion, there are 2 ways that you can change therapy with high level evidence. One is to do a randomized control compared with standard of care and number 2 is staging changes. With PSMA PETS and with improved imaging overall, maybe we need to better define, biologically, what oligometastatic prostate cancer is. If that's true, then maybe we should treat them like metastatic prostate cancers to understand these processes a little bit better and find the optimum treatment recommendations for these patients.

Reference

1. Tang C, Sherry AD, Haymaker C, et al. Addition of metastasis-directed therapy to intermittent hormone therapy for oligometastatic prostate cancer (EXTEND): A multicenter, randomized phase II trial. J Radiat Oncol. 2022;114(5):P1059-1060. doi:10.1016/j.ijrobp.2022.09.006