Home
This site is intended for healthcare professionals
Sign upLog in

Key Clinical Summary: Understanding mechanisms of action of emerging non-chemotherapy agents

This is a micro-learning module summary of a presentation by Dr. Emmanuel Antonarakis which you can find here. Before participating, please read our CME and disclosure information which can be found here.

This activity is supported by an independent medical educational grant from Pfizer. This online education program has been designed for healthcare professionals globally.

Introduction

This summary explores emerging non‑chemotherapy approaches for metastatic castration‑resistant prostate cancer (mCRPC), outlining advances in radioligand therapy, antibody–drug conjugates (ADCs), and bispecific immune engagers. It reviews mechanisms of action, evolving clinical data across key phase 2 and 3 trials, and considerations for integrating these agents into treatment paradigms as the therapeutic landscape expands.

Radioligand Therapies Targeting PSMA

  • Mechanistic principles
    • Radioligands deliver targeted beta‑particle radiation to prostate cancer cells expressing prostate-specific membrane antigen (PSMA).
    • Differences among agents relate to ligand structure, chelators, linkers, and dosing intensity, all of which influence tumor uptake and therapeutic effect.
  • PSMAfore (Lu177-PSMA-617)
    • Evaluated in pre‑taxane mCRPC after one prior androgen receptor pathway inhibitor (ARPI).
    • Standard regimen: 7.4 GBq every 6 weeks, up to six doses.
    • Demonstrated clinically meaningful radiographic progression-free survival (rPFS) benefit over ARPI switch, supporting regulatory approval in this setting.
  • SPLASH (Lu‑177–PNT-2002)
    • Used a lower dose (6.8 GBq), less frequent schedule (every 8 weeks) than PSMAfore, and fewer cycles (up to four).
    • rPFS endpoint met, but hazard ratio was more modest than in PSMAfore.
    • Lower prostate-specific antigen (PSA) response and objective response rates may reflect reduced cumulative radiation exposure.
    • Development will not proceed toward FDA submission.
  • ECLIPSE (Lu‑177–PSMA‑I&T)
    • Dosing aligned more closely with PSMA‑617 (7.4 GBq every 6 weeks; protocol amended to allow six doses).
    • Press release indicates primary rPFS endpoint met; full data pending.
    • Results will clarify whether ligand and linker differences translate into clinically meaningful distinctions.
  • PSMA‑targeted radioantibody (Lu‑177–rosopatamab tetraxetan)
    • Uses a monoclonal antibody rather than a small‑molecule ligand, potentially altering biodistribution and tumor penetration.
    • ProstACT GLOBAL phase 3 trial compares the agent with ARPI switch or docetaxel, enabling evaluation against both hormonal and chemotherapeutic standards.
    • Results will determine whether antibody‑based delivery offers advantages over ligand‑based constructs.

Antibody–Drug Conjugates Targeting B7‑H3

  • Rationale for B7‑H3 targeting
    • B7‑H3 (CD276) is highly expressed in prostate cancer relative to other solid tumors, making it an attractive surface antigen for ADC development.
  • Vobramitamab duocarmazine (MGC018)
    • Delivers a duocarmycin cytotoxic payload.
    • TAMARACK phase 2 trial tested two dose levels (2.0 vs 2.7 mg/kg every 4 weeks).
      rPFS ~9 months in both arms, with PSA50 responses ~40–45%.
    • Development was halted due to high rates of pleural effusion (~30–45%) and pericardial effusion (12–18%), toxicities uncommon in prostate cancer management and challenging to monitor.
  • Ifinatamab deruxtecan (DXd‑based ADC)
    • Also targets B7‑H3 but uses a topoisomerase‑I inhibitor payload.
    • Demonstrated objective radiographic responses across multiple tumor types, including mCRPC.
    • Toxicity profile appears more manageable, with predominantly grade 1–2 nausea, vomiting, fatigue, and anemia.
    • Advancing to phase 3 evaluation in first‑line mCRPC against ARPI switch or docetaxel.

Bispecific Immune Engagers

  • Mechanistic principles

    • Bispecific T‑cell engagers link CD3‑positive T cells to prostate cancer cells expressing specific surface antigens, promoting targeted cytotoxicity independent of major histocompatibility complex (MHC) presentation.

  • Xaluritamig (AMG 509; STEAP1 × CD3)

    • STEAP1 is highly expressed in prostate cancer and minimally expressed in normal tissues.
    • Phase 1/2 data with xaluritamig show PSA50 responses in ~50% of patients and PSA90 responses in ~30%.
    • Activity observed in nodal, osseous, and visceral metastases, including liver lesions.
    • Phase 3 development is ongoing in later‑line mCRPC, with plans to move earlier in the disease course.

  • Pasritamig (KLK2 × CD3)

    • Targets KLK2, a prostate‑specific kallikrein related to PSA (KLK3).
    • In a phase 1 trial, pasritamig demonstrated meaningful PSA reductions with dosing every 6 weeks.
    • Phase 3 studies are underway in second‑ and third‑line mCRPC, with potential expansion into earlier settings.

Emerging Agents In The Future Treatment Landscape

  • Mechanistic diversity

    • Radioligands, ADCs, and bispecifics offer distinct mechanisms that may overcome resistance to ARPIs and taxanes.

  • Biomarker‑driven selection

    • PSMA expression, B7‑H3 expression, and STEAP1/KLK2 status will increasingly guide therapy sequencing.

  • Toxicity considerations

    • Effusion risk with duocarmycin‑based ADCs, cytokine‑related effects with bispecifics, and marrow suppression with radioligands require tailored monitoring strategies.

  • Positioning in the treatment landscape

    • As phase 3 data mature, these agents may shift from late‑line to earlier‑line therapy, particularly for patients with visceral disease or ARPI‑refractory progression.

Conclusions
Emerging non‑chemotherapy agents are reshaping the therapeutic landscape for mCRPC. Radioligands continue to expand beyond PSMA‑617, with multiple agents refining dosing, ligand structure, and delivery platforms. B7‑H3–directed ADCs demonstrate proof of concept, with next‑generation constructs such as ifinatamab deruxtecan offering improved tolerability. Bispecific immune engagers targeting STEAP1 and KLK2 show substantial early activity, including in visceral metastases, and are advancing rapidly through clinical development. Together, these modalities provide new mechanisms to address resistance, broaden therapeutic options, and support more personalized treatment strategies for advanced prostate cancer.

Content is accurate as of the date of release on 2 March 2026.