Daily highlight in prostate cancer

Reported by Dr Marco Gizzi, GHDC & Cliniques Universitaires Saint-Luc, Brussels

Marco Gizzi, medical oncologist working at the Grand Hôpital de Charleroi and in Clinique Universitaires Saint-Luc, Brussels, had the privilege to present the highlights on prostate cancer during the ESMO 2023 congress. He was so kind to share his selection here also.

RADICALS RT was a randomized controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7–10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy. The aim was to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for PSA biochemical progression. The final analysis showed that for metastasis-free survival and overall survival, no benefit was seen for adjuvant radiotherapy. Also, the toxicity remains higher with adjuvant as compared to early salvage therapy. Based on these outcomes, it’s probably the end of adjuvant radiotherapy. Only one-third of patients in the trial had high-risk features, so probably for those patients, adjuvant radiotherapy can still be discussed with the patient, keeping in mind it’s more toxic.

During the presidential session, Dr. Oliver Sartor presented the PSMAfore trial, a phase 3 trial involving ¹⁷⁷Lu-PSMA-617 (LuPSMA), a targeted radioligand therapy for PSMA-positive mCRPC. This trial included taxane-naive mCRPC patients who showed PSMA PET positivity after conducting a PSMA PET scan. Importantly, they were candidates for a change in ARPI after one progression on prior ARPI, knowing that a change in ARPI is currently not a standard of care in this indication due to known cross-resistance between enzalutamide or abiraterone. Randomization was 1:1 to open-label LuPSMA for 6 cycles or ARPI change. Patients randomized to ARPI could crossover to LuPSMA-617 following centrally reviewed radiographic progression. The primary endpoint of rPFS was significantly improved with an impressive hazard ratio and a doubling of the median rPFS. The data for OS are immature for now, but the pre-specified subgroup analysis showed a favourable trend for OS. Lu-PSMA has the potential to become a new standard of care in this indication for very well-selected patients.

ENZA-p (ANZUP 1901) is an open-label, randomized, two-arm, multicentre, phase 2 trial, randomly assigning mCRPC patients at high risk of early progression, to enzalutamide plus LuPSMA or enzalutamide alone, which is a standard of care in this indication. The PSA progression-free survival was improved, with an impressive hazard ratio in this indication. Safety data are reassuring. This is only a phase two trial, but the first randomized trial using a combination of LuPSMA and an ARPI.

Two phase 3 trials on immunotherapy with a similar design were presented. The KEYNOTE 641 trial was in the mCRPC setting, where patients were randomized to receive pembrolizumab and enzalutamide or enzalutamide alone. The KEYNOTE 911 has the same design but in the mHSPC setting. Both trials failed to improve their primary endpoint of OS and rPFS and showed increased toxicity in the combination arm. In an unselected population of both mHSPC and mCRPC, the combination of immune-checkpoint inhibition and enzalutamide was clinically ineffective and more toxic than enzalutamide monotherapy, which is a standard of care in this indication.

Luckily, the future might be bright for immunotherapy in prostate cancer thanks to the T-cell engagers. These are new molecules with a new mechanism of action that is now in early clinical trial development. AMG 509 is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. An interim analysis demonstrated encouraging anti-cancer activity with partial responses in all the cohorts in one out of four patients, increasing to 40% in the high-dose cohort.  The safety profile was manageable.

References:

Noel Clarke – Timing of Radiotherapy (RT) After Radical Prostatectomy (RP): Final Results of RADICALS RT Randomised Controlled Trial [NCT00541047]. ESMO23 – 1764O

Louise Emmett – Enzalutamide and ¹⁷⁷Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer (mCRPC): a randomised, phase 2 trial: ENZA-p (ANZUP 1901). ESMO23 – LBA84

Oliver Sartor – Phase 3 trial of ¹⁷⁷Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). ESMO23 – LBA13

Christian Gratzke – Pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): randomised double-blind phase 3 KEYNOTE-991 study. ESMO23 -1772MO

Julie N. Graff – Pembrolizumab (pembro) plus enzalutamide (enza) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): randomised double-blind phase 3 KEYNOTE-641 study. ESMO23 – 1771MO

William Kelly – Interim Results From a Phase 1 Study of AMG 509 (xaluritamig), a STEAP1 x CD3 XmAb 2+1 Immune Therapy, in Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC). ESMO23 – 1765O