Failed Docetaxel, Failed Pluvicto...Now What?

If you have neuroendocrine prostate cancer, then you wanna look for a DLL three trial. That is after you have tried cabazitaxel with Carboplatin

Otherwise, about the only thing available are clinical trials

Clinical trials CRPC treatments when all else fails new treatments

The study focused on men with metastatic castration-resistant prostate cancer – an aggressive form of the disease that has spread and no longer responds to hormone-blocking treatments.
https://www.news-medical.net/news/20260515/Multi-institutional-trial-explores-new-lifeline-for-advanced-prostate-patients.aspx
Developing effective therapies for prostate cancer bone metastasis—a final stage of prostate cancer progression without any effective treatments—is a medical priority,”
https://www.masseycancercenter.org/news/2026/innovative-targeted-therapy-halts-prostate-cancer-spread-to-the-bone/
promising antitumor activity with combination of pasritamig and docetaxel in advanced prostate cancer
https://www.jnj.com/media-center/press-releases/early-study-results-from-johnson-johnson-show-promising-antitumor-activity-with-combination-of-pasritamig-and-docetaxel-in-advanced-prostate-cancer
Experimental treatment kills prostate tumor cells while reawakening antitumor immunity
https://news.cornell.edu/stories/2026/06/experimental-treatment-kills-prostate-tumor-cells-while-reawakening-antitumor
Early study results from Johnson & Johnson show promising antitumor activity with combination of pasritamig and docetaxel in advanced prostate cancer
https://www.jnj.com/media-center/press-releases/early-study-results-from-johnson-johnson-show-promising-antitumor-activity-with-combination-of-pasritamig-and-docetaxel-in-advanced-prostate-cancer
Experimental treatment kills prostate tumor cells while reawakening antitumor immunity
https://news.cornell.edu/stories/2026/06/experimental-treatment-kills-prostate-tumor-cells-while-reawakening-antitumor
Roswell Park Study: Inhibiting Regulator Protein Can Make Aggressive Prostate Cancers More Vulnerable.

BCL2 inhibitors in combination with a lutamide
https://physicianresources.roswellpark.org/news/roswell-park-study-inhibiting-regulator-protein-can-make-aggressive-prostate-cancers-more-vulnerable
Tiny silica particles wiped out aggressive prostate cancer in mice
https://www.sciencedaily.com/releases/2026/07/260708022158.htm
Researchers Uncover a Promising New Way To Stop Prostate Cancer From Spreading
https://scitechdaily.com/researchers-uncover-a-promising-new-way-to-stop-prostate-cancer-from-spreading/
I attended a presentation yesterday of an extremely interesting treatment for prostate cancer that is in phase 2 trials. It involves using a probe they put directly into a metastasis and it freezes the center, and then they put in a drug that spreads throughout the body and kills all metastasis. It’s been very successful in trials, they are using three different doses right now and trying to figure out which two should be part of the third phase of the trial.

you can find out more information about this trial and maybe even sign up for it at this website
https://legion100trial.com
The result: vitamin E supplementation increased prostate cancer risk by 17%.

New antibody drug stops aggressive prostate cancer from
spreading
https://www.sciencedaily.com/releases/2026/07/260718010151.htm
Optimizing Care for Patients With Metastatic Castration-Resistant Prostate Cancer
https://ascopubs.org/doi/10.1200/EDBK-26-516658

Where has your prostate cancer spread to: tissue only; tissue and bone; bone only?

In what country are you located? Is Actinium-225 approved where you live?

Are you a candidate for immunotherapy?

Are you a candidate for PARP inhibitor therapies?

There are combination regimens that are available:
> enzalutamide (Xtandi) with talazoparib (Talzenna): https://www.cancer.gov/news-events/cancer-currents-blog/2023/fda-talazoparib-enzalutamide-prostate-cancer

> Akeega (Zejula (niraparib) with Zytiga (Abiraterone)): https://www.onclive.com/view/novel-combination-regimens-are-expanding-the-prostate-cancer-treatment-paradigm

A couple of years ago, there were a number of therapies being studied (see attached chart from a Mayo Clinic webinar). You might want to follow up to see if any of these panned out.

When treatments stop working: https://www.everydayhealth.com/prostate-cancer/prostate-cancer-treatment-what-to-do-when-it-stops-working/

As always, discuss all this with your doctor.

As @jeffmarc has illustrated, there are clinical trials which might accept you; but waiting to get into some of them can be a problem.
Have you asked your MO about BAT - an alternating regimen of ADT and Testosterone (yes, that’s it) which can ‘confuse’ cancer cells and trick them into not growing or spreading. Often called Bi-Polar treatment.
As with everything PCa related, sone men react highly favorably and others not so much. It is ‘however’ worth a shot. Best,
Phil

@jeffmarc Thank You Jeff