One-Size-Fits-All Treatment Is Not Appropriate in Node-Positive Prostate Cancer

Jason Zhu, MD

Certain patients with pathologic node-positive prostate cancer are suitable for active surveillance, whereas other patients with higher-risk disease should receive androgen-deprivation therapy (ADT) plus radiation, said Jason Zhu, MD, who added that personalized therapy is also required in clinical node-positive disease wherein abiraterone acetate (Zytiga) could be added to ADT and radiation for patients with aggressive disease.

“[Men with] pathologic node-positive and clinical node-positive [prostate cancer] are very heterogeneous populations,” said Zhu. “That is why there is no one-size-fits-all approach. We need to personalize treatment.”

“For patients with pathologic node-positive disease, close observation is reasonable in patients with a PSA [prostate specific antigen] of 0 after surgery. However, most patients should get ADT plus radiation,” added Zhu. “In addition to ADT and radiation for most patients with clinical node-positive disease who are fit, I give abiraterone for those with more aggressive Gleason scores. Otherwise, if a patient is more fragile, ADT and radiation alone is reasonable.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on prostate cancer, Zhu, a medical oncologist at the Levine Cancer Institute of Atrium Health, discussed the need to tailor therapy with ADT, radiation, and antiandrogen agents for men with pathologic and clinical node-positive prostate cancer.

OncLive^®: Historically, how had ADT been utilized for patients with pathologic node-positive prostate cancer and how has it changed in the modern era?

Zhu: For patients who have pathologically [positive] nodes after surgery, we only have 1 prospective, randomized trial that addressed [the utility of ADT]. That [trial provided] the only level 1 evidence we have. [It was a] very small study published in the New England Journal of Medicine in 1999 that evaluated 98 men. [The trial was conducted] in an era where PSA [was not evaluated] as frequently before or after surgery.

In this randomized study, [the investigators] found a significant difference between overall survival [OS] for men who started [hormonal therapy] immediately vs men who had delayed ADT. The [investigators administered treatment] when men developed bone metastases.

In the current era, that is not exactly how everyone [approaches treatment]. Frequently, we now start ADT much sooner. We look at the PSA doubling times and follow [patients] for biochemical recurrence. We will frequently start [ADT when a patient has] a short [time to] biochemical recurrence.

It is not necessarily the current population [we see in practice], but [the trial] did show that if patients were started [on ADT] early, that seemed to provide an OS benefit.

Have we seen any new data evaluating ADT that can help guide current treatment decisions?

In the modern era, we know that there may be a subset of men who actually can be safely observed [rather than given ADT]. A couple of large retrospective studies followed patients who had lymph node metastases and were then observed. About 20% to 30% of men with node-positive disease didn’t have biochemical recurrence, even at 10 years [of follow-up]. We have looked into why that happens and found that there are certain low-risk patients who we can predict for. These are patients with a Gleason score of 6 or 7 who have less than 3 [positive] nodes. It is reasonable to observe these patients if [the goal is to] hold off on systemic therapy because we may be sparing one-third of men [from unnecessary treatment].

What factors do you consider when determining whether a patient can be safely observed or needs ADT plus radiation therapy?

The main [factor] I look at first is whether a patient has achieved a PSA of 0 after surgery. If the patient has rising PSA after surgery with node-positive disease, they should be referred for radiation, as well as ADT. For most of these men, I treat them for a minimum of 2 years with ADT.

If the patient does achieve a PSA of 0, then we have to look at the overall clinical picture and their pathology. If the patient had a Gleason score of 6 and only 1 or 2 positive nodes, it is reasonable to observe [the patient] and follow [them] closely in clinic. At the time of biochemical recurrence, we can think about radiation or ADT.

For men with a PSA of 0 but more intermediate- or high-risk disease [features], such as a Gleason score of 7 or higher or more than 2 [positive] nodes, we can have a discussion about ADT plus radiation. Most of these men are going to see systemic therapy and radiation in the future.

What efficacy has abiraterone demonstrated in patients with clinical node-positive disease?

As we know from the STAMPEDE and LATITUDE trials, [treatment with] abiraterone showed an increase in OS and progression-free survival [PFS] for men with metastatic hormone-sensitive prostate cancer. It brought this drug from those 2 studies to that setting from the castration-resistant setting.

In STAMPEDE, a small subset of about 180 men in each arm were node positive, but nonmetastatic. In that small subset—for which the study was not powered to look at—there was no difference in OS per the initial analysis. Although the data are immature, only about 78 events [occurred]. However, there was a significant failure-free survival with a hazard ratio [HR] of about 0.2, which included PSA progression and clinical radiographic [progression].

Therefore, there is a subset of men who may be younger with more aggressive disease that could benefit from abiraterone in that clinical node-positive setting.

How has the combination of docetaxel and zoledronic acid plus long-term hormone therapy affected patient care?

That data for docetaxel and zoledronic acid also comes from the STAMPEDE trial, but an early iteration of the trial. [The combination was] compared with ADT vs ADT plus docetaxel. In that study, there was no difference in OS. There was a slight benefit in PFS, although the HR was not as impressive [as in the STAMPEDE trial] at 0.6.

Giving docetaxel is more toxic; it [is associated with] more adverse effects. Most of us are nervous to use docetaxel in this setting [for men with node-positive prostate cancer] and prefer [to use] abiraterone.

How do you select between these regimens for patients with node-positive disease?

For patients with clinical node-positive disease, I first like to know what their Gleason score is based on their original prostate biopsy. If their Gleason score is 6 or 7, I generally give ADT plus radiation therapy. However, [if] they have more aggressive disease [with a] Gleason [score] of 8 or higher, but are otherwise fit and healthy patients, I add abiraterone. There is benefit in preventing the development of metastases, which can be quite morbid.

If their Gleason [score] is greater than 8, but they have many other medical comorbidities, such as uncontrolled atrial fibrillation or other cardiac toxicities, then it is reasonable to [give] ADT plus radiation.

Looking forward, what research efforts need to be made in order to ensure that treatment strategies are tailored to individual patients?

We know we have data that include Gleason score, number of [positive] nodes, positive margins, and other [similar factors]. However, the next step is our advanced imaging. As PSMA [prostate-specific membrane antigen] PET is finally getting to the [clinical setting in] the United States, we should see more trials using that imaging technique, which is more sensitive and specific compared with our current standard CT and bone scans. By using that approach, we will be able to further tease out which patients are more high risk and need additional therapy and radiation vs those who are lower risk and can be safely observed.