Front-Line Treatment Options for Patients with mCRPC


Dr Matthew Rettig reviews the front-line treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) and what factors are considered when choosing appropriate treatment.

Alicia Morgans, MD: Matt, I’m wondering if you can talk to us about some of the available frontline treatments for patients with metastatic castration-resistant prostate cancer [CRPC]. There have been a lot of shifts, and there’s a lot of data coming out. What’s available to us now?

Matthew B. Rettig, MD: Metastatic castration-resistant prostate cancer is a huge topic, and it is constantly changing. It’s constantly changing in large part, not only because we are identifying new therapies, but also some of the older therapies that we used to use only in patients with metastatic castration-resistant prostate cancer are now being moved to metastatic castration-sensitive prostate cancer, where they have an even greater effect. But as a general rule, there are a number of treatments that can be used in the metastatic CRPC space. Typically, the first drugs that we use are hormone therapies. The idea here is that castration, again, not the most palatable term, lowers testosterone, but the tumor can still activate the hormonal environment, the hormonal milieu, through various adaptations, and therefore the tumor is still dependent upon the hormonal environment. We have other hormone therapies, pills, which can be used for patients with metastatic castration-resistant, prostate cancer. How well they work depends on how much treatment they’ve had in the metastatic castration-sensitive space.

We also have chemotherapy. There are chemotherapy drugs that can be used. In fact, chemotherapy was the first type of treatment that had ever been shown to prolong life expectancy in metastatic CRPC, and that was way back in 2004. Now we have these other, newer hormonal therapies. I’ll mention enzalutamide and abiraterone; they go by the brand names Xtandi and Zytiga. And we have chemotherapy with docetaxel or taxotere. There’s another chemotherapy that can be used after that called cabazitaxel, a close cousin to docetaxel, and its brand name is Jevtana. We also have a cellular vaccine that can be used very early in the castration-resistant setting.

We also have something called radium-223. Radium is a calcium mimetic, so it’s very like calcium, and like calcium, it homes to bone where there’s new bone formation. Bone formation occurs at the sites in the bone where the prostate cancer is, that’s how the bone reacts to prostate cancer cells. So when we give a radioactive form of radium, it homes to the bone where the cancer is and can be very effective. That’s a treatment that is delivered not by the medical oncologist, but by our nuclear medicine colleagues like Dr Calais.

We also have some new therapies that are based upon genetic tests and mutations that are detected by genetic tests, whereby we can match a drug to a specific mutation. Genetic testing of patients and their tumors is an important part of the treatment landscape for metastatic CRPC. We have drugs called PARP [poly ADP ribose polymerase] inhibitors. We also have immunotherapies called checkpoint inhibitors that can be used in a small subset of patients, but those are really premised on genetic testing.

Finally what’s really new, hot off the presses is PSMA [prostate-specific membrane antigen]-based treatment. We call it radioligand therapy, and like the PET [positron emission tomography] scan, it leverages the fact that PSMA is overexpressed, it’s found with an increasing concentration on the surface of tumor cells. That can be exploited not only for the PET scanner as we already discussed, but also for treatments. You may have heard it called Lu 177 or lutetium PSMA. What we’re really referring to is radioligand therapy, which has an FDA [United States Food and Drug Administration] approval for patients who’ve already had chemotherapy. And now we’re testing it in earlier stages of the disease, as we will discuss.

Alicia Morgans, MD: Wow, that is quite a list. I think you and I will stay employed for a while because it’s hard to sort through all those things. But I’d love it if you could share some of the general principles that you use when you’re choosing between these. Do you throw a dart at this long list? Are there things that you’re considering otherwise?

Matthew B. Rettig, MD: Ultimately, we do want to practice precision oncology, and some of that precision is based on a genetic test. Some of it is based upon the patient, clinical factors and certain features, even certain racial factors, where certain races may respond to one treatment better than the other. Then what prior treatments the patient has had, and factors about the disease. How fast is it progressing? What organs is it involving? How does the patient feel? Are they suffering from their cancer? Do they have pain? Do they have a loss of appetite? We put all of this information into our computer brains, and we try to come up with the best treatment for the patient. Sometimes there are many options, and sometimes there are fewer, but it all depends upon the individual patient and their specific context. That comes with judgment and experience, and as you know, Alicia, it can be a challenge for both patients and physicians to come up with a shared decision about what’s the best next treatment.

Alicia Morgans, MD: I agree with you, and there are so many things to think through. Like you said, the patient’s preferences are always things that we include in that decision-making process. Are there some drugs that you think of as being later line vs you mentioned using hormonal therapies maybe early on? What are the things you’re thinking about in later lines and onward?

Matthew B. Rettig, MD: In general, I tend to use chemotherapy later in line when patients are more symptomatic. Of course, chemotherapy can have more side effects, and patients understandably don’t necessarily want to have chemotherapy. I tend to reserve that for later in the disease course. But ironically, chemotherapy has also been tested for patients with metastatic castration-sensitive prostate cancer, where it has an even greater impact on the outcome than reserving it for the late stages of castration-resistant prostate cancer.

Alicia Morgans, MD: It is definitely all shifting. You mentioned that we try to shift the mechanism of action too, as we’re going line to line to line. So having all of these different mechanisms of action can be so important and helpful.

Transcript edited for clarity.

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