For patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on triplet therapy, taxane-based chemotherapy remains a common treatment option. However, many clinicians are reaching for alternatives to chemotherapy, including metastasis-directed therapy (MDT) and prostate-specific membrane antigen (PSMA)–targeting radioligand therapy (RLT).

In a lot of situations, I think that the clinicians who wind up treating patients with another taxane after triplet therapy are those who do not have access to therapies such as the RLT ¹⁷⁷Lu-PSMA-617. Chemotherapy is an effective treatment, but it is tough on the patient. In a Canadian study in patients with mCRPC presented at the European Society for Medical Oncology (ESMO) Congress 2025, it was surprising that ¹⁷⁷Lu-PSMA-617 did not perform better than docetaxel; the radiographic progression-free survival for the 2 treatments was similar. But really, the tolerability issue is why many of us would not give more chemotherapy to a patient who has already undergone chemotherapy. It is just something that patients typically do not want.

So, I think that there are 2 main considerations when deciding to re-treat with chemotherapy. One is, of course, quality of life, which is really important to patients. The other is the need to switch mechanisms of action, as you are more likely to get a longer-term benefit if you switch to a drug that works in a completely different manner.

After triplet therapy, many patients present with oligometastatic disease; they progress slowly with a small number of sites and are often asymptomatic. So, it does raise the question of whether we treat them with MDT. For some, MDT works for a long time. You just radiate the lesions, and it works for 1 or 2 year(s).

I think that the LUNAR trial comparing stereotactic body radiation therapy alone with the addition of ¹⁷⁷Lu-PNT2002 to stereotactic body radiation therapy in patients with oligometastatic hormone-sensitive prostate cancer was interesting. LUNAR was a small, randomized, phase 2 study out of the University of California, Los Angeles. Even though there was a relatively low volume of disease, time to progression was significantly delayed with ¹⁷⁷Lu-PNT2002 treatment. This suggests that PSMA-targeting RLT may be targeting microscopic disease.

This is exciting because early studies in mCRPC suggested that PSMA-targeting RLT does not work if you do not have visible lesions. I think that the reason it does not seem to work in some patients with mCRPC, because it does not “light up” on a positron emission tomography/computed tomography scan, is because these cancers no longer rely on PSMA. They are not PSMA expressors. In contrast, in the earlier disease or oligometastatic setting, it is not that they do not express it, but rather we just do not see it. That is the key difference.

Overall, the concept of treating with a second taxane for progression after triplet therapy has been around forever—ever since cabazitaxel became available. However, in my practice, this is not what I would reach for first, unless the patient had a very aggressive non–PSMA-producing tumor, such as a neuroendocrine tumor.