Ask the Experts – Scott E. Eggener, MD

Question 1. What do you make of the studies looking at cytoreductive radical prostatectomy?

Answer
There is a lot of enthusiasm about the potential role of cytoreductive prostatectomy to improve long-term cancer outcomes and lower the chance of long-term local cancer-related symptoms. These 3 studies provide new data, which add to the conversation, but by no means generate definitive answers or solidify the role of cytoreductive prostatectomy as a standard of care.

In one of the studies (PD57-12), the investigators looked at the effect of cytoreductive prostatectomy on PSA in men without prior neoadjuvant ADT. By definition, a cytoreductive prostatectomy is for patients who have disease elsewhere, so I have a hard time understanding how it was possible to have an undetectable PSA without neoadjuvant ADT. Nevertheless, their conclusion is basically self-evident: the better the PSA response after surgery the better the long-term outcomes.

[In the study, 47% of patients had PSA persistence after cRP and 53% did not. The 5-year clinical recurrence- and cancer-specific mortality rates were 49% and 83%, respectively].

In another study of men with metastatic castration-sensitive prostate cancer (PD16-02), it certainly is encouraging, with modest follow-up [median 43.7 months], that there weren’t any local relapses following cytoreductive prostatectomy. The study adds information about what we already know about functional return, with two-thirds of patients needing no pads or one pad and one-third having more significant incontinence.

All in all, it’s great researchers are collecting data and incrementally adding useful information. The big ticket data are really going to come from larger randomized studies, such as SIMCAP (Surgery in Metastatic Carcinoma of Prostate), SWOG study, TroMbone (Testing Radical prostatectomy in men with prostate cancer and oligoMetastases to the bone), and others. These will give us definitive answers.

Question 2. Two phase 2 studies examined the effect of neoadjuvant hormone therapy prior to RP. One study was a randomized 3-arm trial (apalutamide followed by RP, GnRH agonist+ apalutamide + abiraterone followed by RP, and RP alone) and the other was a single-arm trial of neoadjuvant apalutamide. Both suggest that neoadjuvant hormone therapy has positive effects on outcomes. How would you characterize the evidence supporting the use of this management strategy?

Answer
There’s a strong rationale of combining more potent androgen axis inhibitors along with surgery. The easiest comparison is that androgen ablation plus radiation therapy works better compared with radiation alone for certain high-risk prostate cancers. We hope combining antiandrogens with surgery can lead to better outcomes, but historically they haven’t. It’s a pretty similar story with these 2 studies.

Most randomized 3-arm trials wouldn’t even allow reporting at this early stage. Each study arm had only a small number of men [2 arms had 7 patients and 1 arm had 10]. The researchers report tumor volume reduction by MRI, which would be expected. There weren’t any complete responses pathologically, which we already know from other trials is very rare. Kudos to the investigators for doing these trials and collecting the data, but there’s really no clinical take-home message. The studies really just set the table awaiting mature data from these and other trials to learn whether this will ever become a standard of care.

Question 3. New data from a team at Mayo Clinic suggest that metabolic PET/CT scans may be able to predict which men receiving primary docetaxel chemotherapy will respond to the treatment (abstract MP37-14). What do you think of this approach?

Answer
This is intriguing. A holy grail is to be able to identify treatment failures earlier and potentially pivot to other more effective therapies. What the investigators were able to show retrospectively is that a choline-PET response mid-treatment does seem to correlate with progression-free survival with a fairly dramatic difference: median 34 months for those with a complete response compared with 9.5 months for those with an incomplete response. This was a stronger predictor compared with a PSA response. [Patients who had a 20% or greater reduction vs a less than 20% reduction in corrected SUVmax on mid-course scans were 3.6 times more likely achieve a complete response after a full 6 cycles of docetaxel.]

However, the study didn’t report how many patients achieved a 20% or higher reduction in SUVmax. These are early data and they’re important, but the most important consideration in the early identification of patients who are not responding to treatment is whether there is a benefit to stopping that treatment and moving on to another one. The study might have identified men with aggressive disease, and no matter what you gave them they would do poorly. An intriguing study design would be PET identification of those with incomplete response and then randomize those men to 2 different regimens.

Question 4. A modeling study (abstract PD62-08) demonstrated that AS vs immediate RP for patients with favorable intermediate-risk PCa is associated with a modest increase in cancer-specific mortality. For example, for 15-year survival, assuming the risk of cancer-specific mortality for men on AS was 1.5 times greater compared with those treated with RP, the estimated excess risk of a cancer-related death was 1.09%. What does this study add to the discussion about the use of AS for this patient population?

Answer
Although we have made tremendous strides [in treatment], I believe more men with low-risk disease should do active surveillance. The next frontier is determining which men with intermediate-risk prostate cancer can benefit from surveillance. There are a lot of series showing impressive long-term outcomes but there still are a relatively small percentage of men who are going to ultimately die of their disease if they go on surveillance. This well-established research group [from multiple centers] looked at 920 men undergoing surgery who met criteria for favorable intermediate-risk prostate cancer. Their modeling suggests surveillance is a very attractive strategy for many of these men. Even if the death rate from surveillance is twice as high compared to surgery, you still have to operate on a whole heck of a lot of men with favorable intermediate-risk prostate cancer to save 1 life. It’s fairly humbling for a prostate cancer surgeon, such as myself, where we treat a lot of men with intermediate-risk cancer, and you look at the data and say, “Gee, you’ve got to treat 46 men to maybe save 1 from dying of prostate cancer over the next 15 years.” Many men with intermediate-risk prostate cancer can benefit from surveillance, and even if we immediately treat them with surgery or radiation, you’re treating a lot of men to save that one man’s life.

Question 5. Do you recommend AS for your patients with favorable intermediate-risk prostate cancer?

Answer
I discuss it as an option for all men with intermediate-risk prostate cancer and I do my best to quantify the likelihood of their developing metastasis or dying while on surveillance. Among men with intermediate-risk prostate cancer, I tell some there’s a 3% to 5% chance of life-threatening outcomes over the next 15 years, and many men are okay with that and choose to do surveillance rather than treatment. For other men, that 3% to 5% is too high and they choose treatment. At the other end of the spectrum, there are men with intermediate-risk prostate cancer who I tell there is a 25% to 30% chance of metastasis or death over the next 10 or 15 years, and almost all of those men elect to have treatment to try to lower that percentage.