Metastatic Castrate-Resistant Prostate Cancer Treatment: Updates on Use of Darolutamide - Episode 2

Systemic Therapy Options in Metastatic Castrate-Resistant Prostate Cancer

An oncologist explains treatment selection and the systemic therapy options available for patients with metastatic castrate-resistant prostate cancer.

Karim Fizazi, MD, PhD: For most asymptomatic men with metastatic castration-resistant prostate cancer, if they have only received previous androgen deprivation therapy [ADT], which is becoming rarer, the main treatment to be considered is a next-generation hormonal agent, such as abiraterone or enzalutamide. For some of them, basically those with liver metastasis or those very rapidly progressing while on ADT, chemotherapy with docetaxel should probably be an important option to consider. If the patient has exhausted an AR [androgen receptor] drug and if they are asymptomatic, you may consider using chemotherapy with docetaxel, but actually many men are not necessarily willing to go for docetaxel chemotherapy. This is the setting where many ongoing phase 3 trials are taking place because this is truly an unmet need for these men with asymptomatic disease, who don’t want to go for chemotherapy. We need probably more options for these men.

In terms of mechanisms of action and more generally, targets, it’s striking the way that things have been changing in the last 1 to 2 decades. In 2000, we were targeting only the androgen receptor axis with what we had at the time, androgen deprivation therapy, and some weaker drugs, such as bicalutamide, flutamide, and others. Based on the data in 2004, taxane showed efficacy. Sixteen or even more years afterward, we still don’t completely understand how taxanes work and what we are exactly targeting when using a taxane.

Part of the efficacy is probably related to the trafficking in the cells. Part of it might be the trafficking of the androgen receptor, but honestly we don’t know the exact mechanism. In the last years, we saw a new target appearing. Obviously, bone targeting has been there for at least a decade, but now DNA defect repair is a potential target for some patients, and we now have direct evidence that PARP inhibitors work in these patients with DNA repair defects. This is now approved with olaparib and hopefully soon with some other drugs.

In 2021, we showed for the first time that targeting PSMA [prostate-specific membrane antigen], which is a quite specific protein for prostate cancer cells, actually makes a difference, including overall survival improvement for these men, with lutetium-177 PSMA-617. I suspect that soon we will see more ways to target PSMA, using for example, PSMA BiTEs [bispecific T-cell engagers] and hopefully some other ways, maybe ADCs [antibody-drug conjugates]. Starting from AR targeting, we’ve moved to potentially other targets being shown as important, at least for some categories of patients.

The beauty is that AR targeting is probably coming back again. We’ve seen at least 2 generations of AR-targeting agents. The first one would be probably androgen deprivation therapies. Second would be abiraterone, enzalutamide, darolutamide, and apalutamide. I suspect we’re about to see a third-generation drug working when [abiraterone] or [enzalutamide] or similar drugs don’t work anymore, and we saw examples of such drugs from phase 1 experience in recent congresses. This is the future.

Transcript edited for clarity.