Metastatic CRPC Treatment Armamentarium


A detailed review of the available pharmacologic agents used to treat patients with metastatic castration-resistant prostate cancer.


Scott Tagawa, MD, MS, FACP: As I’m talking to a patient about systemic therapy for advanced disease, I generally say that there are 6 categories: hormonal, chemotherapy, immune, bone-targeted, molecularly selected, and other. Other generally means clinical trials. The backbone of our therapy is generally hormonal or androgen receptor [AR] pathway–targeted. These range from a class that we call ADT, or androgen deprivation therapy, which is either surgical removal of the testicles, a bilateral orchiectomy, or more likely an LHRH agonist or antagonist. Some people call them NHT, or novel hormonal therapy. They’re not so novel anymore, because we’ve had them for decades.

The AR pathway inhibitors, either the AR-signaling inhibitors, such as enzalutamide, apalutamide, or darolutamide, or the CYP17 inhibitors, such as abiraterone, are quite active for patients with advanced disease and may be active for patients with earlier stages of disease as well. There are a number of emerging investigational options that the AR pathway remains the dominant pathway for the vast majority of patients throughout their lifecycle with advanced prostate cancer.

As far as chemotherapy, there are a number of different chemotherapeutics available. Mitoxantrone was the first that led patient-reported outcome improvements including pain, but the taxanes— docetaxel and cabazitaxel—are 2 classic examples of those that have been proven to have survival advantages in phase 3 trials. Platinum chemotherapy is probably the other main one in use, with positive phase 2 data, and just clinical use, as well as inclusion in guidelines. There are other chemotherapeutics, and maybe some antibody-drug conjugates that are emerging. They’re in between.

As far as immunotherapy, the first cancer vaccine, if you will, ever to be approved was for advanced prostate cancer in sipuleucel-T autologous cellular immunotherapy. For a small subset of patients, there’s the approval of pembrolizumab for those who have microsatellite instability or MMR [mismatch repair]. That’s a small subset of patients, but if we don’t look for those patients, then it’s 0. Patients can have deep and durable responses in prostate cancer as well as in other cancers, so that’s important to mention.

As far as bone-targeted therapy, we’ve had a number of supportive care agents in the realm of treating osteoporosis for a long time. Then came zoledronic acid followed by denosumab to improve skeletal-related events. Then came radium-223, which was the first true bone-targeted agent to lead to a survival advantage. Tailing after my comments on looking at different genotypes, we now have truly molecularly selected therapy. Targeted therapy is something that people mention. All of our therapies are targeted. I think of chemotherapy as targeted, with taxanes binding to specific areas on beta-tubulins, for instance.

But if I were to use a different term than targeted therapy and molecularly-selected therapy, broadly speaking, we can say, “With bone scan positivity, maybe something like radium-223.” But in the genomic era, those with DNA repair defects, depending on how we define them or how broadly we lump them, adding up germline and somatic accounts for maybe as many as 1 in 4—at least 1 in 10—who will have an important pathway alteration such as BRCA2, which we know sensitizes to PARP inhibitors.

We have emerging data on PARP inhibitors in combination with AR pathway inhibitors that maybe that combination doesn’t absolutely need a DNA repair defect. But those data are only emerging. The sixth category that I mention to patients is clinical trials. Clinical trials are right for different patients at many different times, including in the first line as we look to improve on what we have. Not only restricted to those with no other options, but those clinical trials may be in the same other categories or maybe totally different categories.

Transcript edited for clarity.

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