Piotr Wysocki: The [177Lu]Lu-PSMA-617 plus enzalutamide combination is active and safe in mCRPC patients, but is it really an option for first-line treatment?

Piotr Wysocki, Professor of Medicine and Head of the Department of Oncology at Jagiellonian University Hospital, shared on LinkedIn:

“Emmet L. et al. have just published interim analysis results of ENZA-p trial in Lancet Oncology. This phase II randomized, open-label study enrolled metastatic castration-resistant prostate cancer (mCRPC) patients not previously treated with androgen-receptor pathway inhibitor (ARPI) or docetaxel. All patients met Ga-PSMA-11 PET-CT (PSMA-PET-CT) eligibility criteria, which were: PSMA-positive disease with an SUVmax of at least 15 at a minimum of one site of disease and SUVmax of at least 10 at all larger sites of disease. Patients were randomized (1:1) to enzalutamide and [177Lu]Lu-PSMA-617 (lutetium) given on weeks 2 and 8 after starting enzalutamide or enzalutamide alone. All participants underwent PSMA-PET-CT- CT at week 12, which determined adaptive dosing of either two or four doses of lutetium (weeks 16 and 24) in the experimental group.

Of 220 screened patients, 26% were deemed ineligible (18% due to low PSMA expression), and finally, 162 patients were randomized. Two doses of lutetium depleted PSMA-expressing cells in 18% of patients, with 82% requiring additional doses.

After a median follow-up of 20 months, the primary endpoint, median biochemical PFS was 13.0 months in the enzalutamide+lutetium group and 7.8 months in the enzalutamide group (HR 0·43, 95% CI 0·29–0·63).
Median clinical PFS – 14.0 v. 9.4 months (HR 0.47, 95% CI 0.32–0.69). Median radiographic PFS – 16.0 v. 12.0 months (HR 0.68, 95% CI 0.45–1.03).

Combining enzalutamide and lutetium resulted in a higher rate of adverse events than enzalutamide alone (any G3 – 11% v. 4%). Still, overall, the toxicity of the combination seemed much lower compared to studies on lutetium monotherapy in heavily pretreated mCRPC patients (TheraP and VISION).

The ENZA-p study demonstrates that combining lutetium with enzalutamide in first-line treatment of mCRPC patients is relatively safe and significantly improves biochemical and clinical PFS with a trend toward improving radiological PFS.

However, in my opinion, several points must be addressed before we move the lutetium to earlier lines of treatment of mCRPC patients.

1. Lutetium has been shown to improve OS only when compared to suboptimal systemic treatment (ARPI rechallenge) in the VISION study.

2. Lutetium has failed to improve OS when compared to active treatment (cabazitaxel) in the TheraP study.

3. Lutetium is a beta-emitter with significant myelotoxicity, especially in patients with multiple bone metastases.

4. Older beta-emitters like strontium or samarium administered to patients with multiple bone metastases resulted in long-term myelotoxicity, impeding the safety of chemotherapy treatment.

5. Will early-line usage of lutetium, especially in patients with multiple bone metastases, preclude the safe and effective use of docetaxel and cabazitaxel?

6. Does the lower-than-expected (compared to VISION and THERA-P studies) myelotoxicity result from the fact that lutetium was administered in the first line or from the fact that patients had only oligometastatic disease in bones (data not provided in ENZA-p)

7. As for now, I will still consider using lutetium in later lines of treatment, especially after utilization of PARPi (if feasible) and standard (OS-prolonging) chemotherapy regimens (docetaxel, cabazitaxel) or in the case of contraindications to chemotherapy use.”

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Source: Piotr Wysocki/LinkedIn

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