Novel agents and clinical trials in castration-resistant prostate cancer: latest updates from 2023 ASCO-GU Cancers Symposium

Abstract

Numerous novel and effective therapeutic agents and clinical trials addressing castration-resistant prostate cancer (CRPC) were reported during the 2023 American Society of Clinical Oncology-Genitourinary (ASCO-GU) Cancers Symposium. Notably, radionuclide drug conjugates (RDC), specifically 177Lu/111In-J591 and 225Ac-J591, exhibited enhanced therapeutic efficacy in treating patients with CRPC. Furthermore, promising treatment approaches for CRPC included dual anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) blockade in rare tumors (DART)-Lorigerlimab, prostate stem cell antigen (PSCA)-directed chimeric antigen receptor (CAR)-T cell immunotherapy-BPX-601, and protein kinase inhibitor (AKTi)-CAPltello-280. We have summarized the latest CRPC treatment strategies presented at the 2023 ASCO-GU Cancers Symposium, along with recent advances in CRPC clinical trials.

To the editor

Each year, the ASCO-GU Cancers Symposium showcases noteworthy developments and innovations in genitourinary oncology. We have comprehensively reviewed such notable advancements in drugs and novel therapies targeting CRPC, as presented at the 2023 ASCO-GU Cancers Symposium.

RDC in prostate Cancer (PCa)

RDC drugs utilize antibodies or small molecules to modulate specific targets and deliver cytotoxic or imaging agents to the target location, resulting in localized radiation from the radioisotope on the target tissue for efficient and precise treatment while minimizing systemic exposure and radiation-induced toxicity to other tissues [1].

In a randomized, double-blinded phase II study, radioactive 177Lu and 111In, combined with ketoconazole or hydrocortisone, was used to label the anti-prostate-specific membrane antigen (PSMA) monoclonal J591 (NCT00859781). The results indicated a significant reduction in prostate-specific antigen (PSA) levels in most patients with non-metastatic CRPC (M0CRPC) treated with radiolabeled J591 and ketone/HC (PSA decline ratio > 50% (PSA50): 82% and 71% in the177Lu and 111In groups, respectively; PSA decline ratio > 90% (PSA90): 50% and 35% in the 177Lu and 111In groups, respectively). Biochemical progression-free survival (bPFS) was 18.67 and 8.87 months in the 177Lu and 111In groups, respectively, with a significantly higher 18-month PFS in the 177Lu group; however, hematologic toxicity was more common in this group [2]. These findings support the development of anti-PSMA radioimmunotherapy for locally advanced PCa; however, the optimal radionuclide and targeting agent remain to be determined.

Another new triple therapy involving 225Ac-J591 (a PSMA-targeted radionuclide therapy), pembrolizumab, and an androgen receptor pathway inhibitor (ARPI) demonstrated a significant PSA response in both phase I/II trials (NCT04946370). After six months of follow-up, 33% (4/12) of the patients remained progression-free. However, 58% (7/12) of the patients developed unexpected cytokine release syndrome (CRS) 7–14 days after treatment, characterized by a morbid rash, fever, and low blood cell count. Nevertheless, patient responses typically improved within one week after discontinuing ARPI. Additionally, typical immune-related adverse events (irAEs) occurred in 33% (4/12) of the patients, all of which were manageable [3].

Table 1 Basic information on novel agents for CRPC patients from ASCO-GU 2023

Table 2 Outcomes of novel agents and clinical trials in CRPC from ASCO-GU 2023

Novel regimens in PCa

A study reported data on lorigerlimab (a DART molecule [4] that enhances CTLA-4 blockade of dual expression while maintaining a maximal blockade of PD-1) in a trial of 42 PSA-assessable patients with mCRPC (35 RECIST-assessable), with an objective response rate (ORR) of 25.7% (9/35). Only four cases were discontinued owing to unrelated fatal adverse events. Lorigerlimab demonstrated a manageable safety profile with encouraging anti-tumor activity in patients with chemorefractory mCRPC (NCT03761017) [5]. Another multicenter trial presented preliminary results of a phase 1 multicenter trial on BPX-601, an autologous PSCA-directed CAR-T cell immunotherapy [6] that enhances T cell potency and persistence by expressing a mature-induced MyD88/CD40 costimulation switch (NCT02744287). A PSA50 response was observed in 42.9% (3/7) of the patients on day 28. Preliminary results based on RECIST indicated a partial response (PR) of 14.3% (1/7) and stable disease of 42.9% (3/7). Disease progression occurred in only 14.3% (1/7) of the patients, and 14.3% (1/7) of the patients maintained stable disease (SD) for > 9 months [7].

In a phase III study, the efficacy of AKTi-CAPltello-280 (effective selective inhibition [8] of AKT1/2/3) in combination with docetaxel was evaluated, and an increase in overall survival (OS) was observed in patients with mCRPC. Although the Phase III trial is ongoing (NCT05348577), the results from the Phase II trial revealed that patients achieved a median OS of 31.5 months, clinical PFS of 7.03 months, and PSA50 rate of 45% (NCT05348577) [9].

Overall, the 2023 ASCO-GU Cancer Symposium showcased significant advancements in the therapeutic area of CRPC, as evidenced by the findings presented in Tables 1 and 2. The symposium highlighted the emergence of many encouraging new drugs and clinical trials, creating the potential for novel treatment strategies for CRPC.