For decades, chemotherapy was the moment many prostate cancer patients feared most because of its toxic side effects. We see this often in our clinic: men seeking us out when chemotherapy is the next step, hoping there may be other options. Chemotherapy works by attacking fast-growing cells, a hallmark of cancer cells. But the price of such systemic therapy can be high, sacrificing other naturally fast-dividing cells along the way. Fatigue, neuropathy, low blood counts, hair loss…

Recent clinical research, however, is reshaping treatment sequencing in advanced prostate cancer. Trials such as PSMAfore (which led to recent FDA approval for earlier use) and ENZA-P, both testing ¹⁷⁷Lu-PSMA prior to chemotherapy, are a significant leap forward for patients—not only because of their treatment effectiveness, but also because of a more favorable tolerability profile compared with traditional cytotoxic therapy.

The VISION trial had already demonstrated the effectiveness of ¹⁷⁷Lu-PSMA radioligand therapy in patients post-chemotherapy. The phase III PSMAfore then showed that ¹⁷⁷Lu-PSMA therapy significantly prolonged radiographic progression-free survival compared to switching to another, different ARPI (e.g., abiraterone or enzalutamide) after the patient no longer responds to the initial hormone therapy (~11.6 vs ~5.6 months). The smaller, phase II ENZA-P study explored combining ¹⁷⁷Lu-PSMA with an ARPI (enzalutamide) earlier in the disease course and demonstrated improved disease control compared with enzalutamide alone.

The PSMAddition trial takes PSMA-targeted therapy one step earlier, using it alongside standard hormone treatment in men with metastatic hormone-sensitive prostate cancer. The study showed that adding PSMA therapy helped keep the cancer under control longer compared with hormone therapy alone, and it may delay the cancer from turning resistant to treatment.

These trials mark another important treatment paradigm shift—a trend towards personalization. All three were image-guided, based on PSMA-PET imaging — meaning treatment is directed by individual tumor biology rather than rigid treatment sequences.

These advances open the door to delaying chemotherapy, at the very least, while still maintaining strong disease control. Prostate cancer care is becoming more targeted, more personalized, and more humane.

If you're facing advanced prostate cancer, a specialist consultation can help determine whether PSMA-targeted options might be right for you.