We previously covered the ENZA-p phase 2 trial, which demonstrated that adding adaptive (response-adjusted dosing) ¹⁷⁷Lu-PSMA-617 to enzalutamide significantly improved PSA progression-free survival (PSA-PFS) compared with enzalutamide alone in men with poor-risk metastatic castration-resistant prostate cancer (mCRPC). A new substudy, now published in Nature Cancer, provides deeper insight into one of the key mechanisms behind this benefit: rapid PSMA upregulation induced by enzalutamide. This phenomenon has been observed in clinical practice for years (and actively implemented in our clinical practice); the ENZA-p imaging substudy now delivers robust prospective data confirming its predictive value and therapeutic implications.

Study Design

The substudy evaluated 154 of 160 treated patients (out of 162 randomized patients). Participants were randomized 1:1 to either enzalutamide monotherapy or enzalutamide plus adaptive-dosed ¹⁷⁷Lu-PSMA-617. All patients underwent a baseline ⁶⁸Ga-PSMA-PET-CT scan. In 154 patients, a second scan was performed on day 15 after starting enzalutamide. The primary focus was the change in whole-body PSMA SUVmean and its association with treatment outcomes, particularly PSA progression-free survival (PSA-PFS).

Main Findings

Early PSMA upregulation is remarkably common. Whole-body SUVmean increased in 68% (105/154) of patients within just two weeks of enzalutamide exposure.

This change proved strongly predictive of benefit from combination therapy:

• In patients with PSMA upregulation, median PSA-PFS was 1 months with the combination versus only 5.8 months with enzalutamide.
• In patients with PSMA decrease, outcomes were similar regardless of treatment arm (~12.5 months with enzalutamide alone vs. ~13.3 months with combination), indicating little added value from the radioligand in this subgroup.

Importantly, the PSMA changes were almost exclusively tumor-specific, with no significant early alterations in physiological PSMA-expressing tissues such as salivary glands or blood pool. This suggests that using an AR pathway inhibitor (ARPI) to induce PSMA expression is unlikely to exacerbate off-target side effects such as xerostomia.

Two Distinct Cancer Cell Phenotypes

The magnitude and direction of PSMA change reveal important biological differences. Larger increases (typically >10%) are associated with more aggressive tumor behavior and rapid progression on enzalutamide monotherapy. This early rise in PSMA appears to be a stress response by the cancer cells when enzalutamide blocks androgen signalling. These tumour types (or rather cancer cell types, tumours tend to be of heterogenous nature) are particularly sensitive to androgen blockade in terms of increasing PSMA on their surface, but they also tend to be more aggressive and quick to adapt. As a result, they often progress rapidly on enzalutamide alone. Adding ¹⁷⁷Lu-PSMA-617 allows us to exploit this stress response and deliver targeted radiation to the cancer cells.

In contrast, tumors that downregulate PSMA early appear more uniformly dependent on androgen signalling. In these cases, enzalutamide effectively suppresses growth, with reduced PSMA expression occurring as a downstream effect. These tumors tend to be less heterogeneous and less reliant on PSMA-driven pathways, explaining the limited incremental benefit from adding ¹⁷⁷Lu-PSMA-617.

Dual Synergistic Mechanisms

The benefit in the upregulation group likely stems from two complementary mechanisms:

1. Increased targeting – higher PSMA expression allows to deliver substantially more radioligands (and thus more radiation) to the tumor cells.
2. Radiosensitization – enzalutamide impairs DNA repair pathways (including homologous recombination) in prostate cancer cells, making them more vulnerable to radiation-induced damage.

In the PSMA-decrease group, radiosensitization appears to play only a minor role because radiation delivery itself is reduced due to lower PSMA expression.

When radiation delivery is independent of PSMA – as with radium-223 (Xofigo), which targets osteoblastic bone metastases – radiosensitization can contribute more meaningfully. This is supported by the PEACE-3 trial, where adding radium-223 to enzalutamide improved both radiographic PFS and overall survival in men with bone-dominant mCRPC.

Clinical Implications and Limitations

This substudy strengthens the rationale for combining ARPIs with PSMA-targeted radioligand therapy and introduces an early, functional biomarker (day-15 PSMA-PET) that can identify patients most likely to benefit from intensification. It also highlights tumor heterogeneity and adaptive responses in mCRPC.

Although performing two PSMA-PET scans in quick succession is a logistical and financial challenge in many settings, this does not diminish the practical value of the strategy. Since nearly 7 out of 10 patients show significant PSMA upregulation within two weeks of starting enzalutamide, many men may still benefit from a short course of AR pathway inhibition prior to ¹⁷⁷Lu-PSMA-617 – even without the second scan.

Conclusion

The ENZA-p substudy confirms that early PSMA upregulation on enzalutamide is both common and clinically actionable. It identifies a high-risk subgroup that derives outsized benefit from combined ARPI + ¹⁷⁷Lu-PSMA-617 therapy through synergistic targeting and radiosensitization. As PSMA-targeted therapies continue to evolve, this work supports a more personalized, biology-driven approach to treatment selection in advanced prostate cancer – the one offered in our clinic.

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Bibliography

Emmett, L., Swiha, M., Papa, N. et al. Predictive value of early PSMA upregulation for the response to enzalutamide ± ¹⁷⁷Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer: substudy of the randomized, phase 2 ENZA-p trial. Nat Cancer 7, 622–630 (2026). https://doi.org/10.1038/s43018-026-01140-3