Case 2: Sequencing Therapy in mCSPC

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Neal Shore, MD, FACS:So you go through 6 cycles of docetaxel. The patient’s PSA [prostate-specific antigen] declines, and he tolerates it well. You get follow-up scans, and there’s a partial response. The PSA is stable a few months out, and your patient says to you, “Well, what’s the plan? I read about this TITAN trial, and apalutamide is now approved. I also know about this LATITUDE trial, and abiraterone is approved. And I’m reading about ENZAMET and ARCHES.”

Jorge Garcia, MD:You know, I don’t think it is a mistake to actually sequence patients with existing data, based on ARCHES with rPFS [radiographic progression-free survival] improvement. I think the bigger question is, I don’t think we truly know if doing that—I think most of us would be concerned about burning that bridge early on. We have the data that we published. Clearly, when you progress after docetaxel, putting in an oral taxane is just not the right approach. Most people actually do better when they do an AR [androgen receptor] or another inhibitor.

But the timing of that remains to be controversial. I’m not opposed to that, but I have even expanded it a bit more. It really depends on what your PSA nadir is. I do believe that the PSA within 6 months from therapy, whether it’s docetaxel or an AR inhibitor, is going to be defining how well you’re going to do over time.

If you’re not on the Taxol, I think that patient may be the 1 who may be more proactive. Maybe you can put the patient on an AR inhibitor? If your PSA is undetectable, I feel more confident you’re going to do better than the average patient. “Let’s just hold tight and see how you do over time.”

Kenneth Kernen, MD:I think Neal brings up a good point. Patients are much more educated now than they were. They do walk into your office saying, “I read about this trial, this trial, this trial.” I just had this guy walk into my office 2 months ago. He is 53 years old, and his PSA was 400 ng/mL—his first PSA. He’s got high-volume disease, and he walked in saying, “Hey, I’ve read about this, this, this, and this.” We worked with our medical oncology guy who I use all the time. We put him on hormonal therapy. He’s getting his 6 cycles. And then we’re going to put him on an AR therapy. He’s young, and wants therapy.

Alicia Morgans, MD:It definitely happens. Throwing the kitchen sink at people is, for some people, probably the right thing to do. But on the other end of the spectrum, what about oligometastatic disease? Everyone takes a deep breath. You know, those are for the high-volume, very intensive patients—young guys we want to be aggressive on. What if you have 2 or 3 spots, or maybe even just 1 or 2 spots of bone-only metastatic disease? Is anyone thinking about metastasis-directed therapy?

Jorge Garcia, MD:Talking about throwing the sink at someone, right? I think the background, for me, of that very important question is, if you look at the STAMPEDE data, remember that the STAMPEDE trial was never intended to differentiate people between low volume and high volume. And the arm in STAMPEDE can look at ADT [androgen deprivation therapy]—docetaxel against ADT-docetaxel plus primary radiation to the tumor, for what was a negative trial, right? When the trial was negative, the investigators of STAMPEDE decided to actually then use the CHAARTED definition and the LATITUDE definition to define if, in fact, primary radiation to the prostate did have an impact in outcome. They then come to find out, yes, for low-volume patients, regardless of whatever definition one uses.

That allows you, to some extent, to start thinking that maybe there are patients with really low-volume disease for whom not only you can impact mortality, but you may also be able to render them free of disease. Memorial Sloan Kettering Cancer Center has very compelling data that demonstrate that around 20% to 30% of patients for whom you throw the sink at them, to some extent, they will be free of prostate cancer within 7 years. I don’t know if that’s good or not.

I think the question then becomes, how do we define oligo? Is it 1, 2, 3? Is it lymph node disease only? Is it lymph node and bone? And what is the best metastasis-directed therapy? Should we do metastasis-directed therapy alone, or should we follow sort of a STAMPEDE style and do treatment intensification? And in the process of that treatment intensification, where it is 12 or 24 months, should we do metastasis-directed therapy? We have the SWOG data, which is the trial that is looking at primary treatment. And we have other data actually randomizing patients with oligometastatic disease to abiraterone-apalutamide against abiraterone, including ADT, and then surgery, for those patients with a primary tumor in place, radiation therapy to the prostate bed, and metastasis-directed therapy. These things are happening as we speak, and a lot of patients, talking about educated consumers, are coming and are asking you those questions right now.

Neal Shore, MD, FACS:That was a really a great summary, Jorge. You described that really nicely. At APCCC [Advanced Prostate Cancer Consensus Conference] just a couple of months ago, this was a hotly debated issue—the definition of oligometastatic disease, the imaging behind oligometastatic disease, and all these ongoing trials. Some are smaller phase II trials that have already reported out, such as STOMP, etc.

You raise a great point. It seems like right now, the biggest benefit is a delay to the onset of the requirement for ADT. That’s a good thing. ADT is not a free lunch. ADT has a lot of associated toxicity to it. Historically, probably more so with urologists, we said, “Oh, well, it’s hot flashes and loss of sexual function.” We clearly recognize the plethora of adverse effects to it. If you do metastasis-directed therapy, you can delay ADT and not put the patient at risk for the long term. That’s quite a good thing.

I get a little concerned if we swing the pendulum back too much, and we don’t do the right trials. For example, you know taking out someone’s prostate who has metastatic disease should really only be done in high-volume, very experienced centers because of the potential for complications. Then you made a really good point too about Chris Parker’s paper inTheLancet. You’re absolutely right. The totality of the trial failed in radiation, but it was in the low-volume group in a secondary analysis that showed the value. We have to be careful about that as well.

Transcript edited for clarity.