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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Advances in Targeted Therapy for Metastatic Prostate Cancer
Kabir Grewal1, Tanya B Dorff2, Sagar S Mukhida3
1Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA.
Opinion Statement:
Over the past few years, treatment for advanced prostate cancer has begun shifting away from a one-size-fits-all approach toward biomarker-based therapies for select groups of patients. This review highlights the role of poly-ADP-ribose-polymerase (PARP) inhibitors in metastatic prostate cancer, emerging strategies to target the androgen receptor (AR), and innovative therapies aimed at cell surface proteins, including radioligand therapies, bispecific T cell engagers, and antibody-drug conjugates. For patients with homologous recombination repair (HRR)-mutated metastatic castration-resistant prostate cancer (CRPC), we favor combining a PARP inhibitor (PARPi) with an AR pathway inhibitor (ARPI), provided they can tolerate a more aggressive treatment strategy. In our opinion, patients with BRCA1 or BRCA2 mutations who are unable to handle combination therapy benefit from PARPi monotherapy. We are enthusiastic about the potential of ongoing clinical trials for new AR-directed therapies, such as AR ligand-directed degraders and CYP11A1 inhibitors, in metastatic CRPC. These treatments are expected to be most beneficial for patients whose cancer continues to rely on AR pathway signaling, suggesting they might also be effective in earlier stages of the disease. Progress in drug development and understanding of protein structures has led to new therapies that target cell surface proteins predominantly found in prostate cancer. We use 177Lu-PSMA-617 for patients with PSMA avid metastatic CRPC who have progressed on an ARPI and a taxane chemotherapy. Additionally, we see promising potential in bispecific T-cell engagers (e.g., STEAP1-CD3 and PSMA-CD3) and novel radioligand therapies, including those utilizing actinium, to target these proteins. These advances show great promise in further enhancing survival for patients with metastatic prostate cancer.
Insights
Biomarker-driven treatments are revolutionizing advanced prostate cancer care. Poly-ADP-ribose-polymerase (PARP) inhibitors and androgen receptor (AR) pathway inhibitors offer new hope, especially for patients with specific mutations.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Advanced prostate cancer treatment is evolving from a uniform approach to personalized, biomarker-guided therapies.
- Key areas of advancement include poly-ADP-ribose-polymerase (PARP) inhibitors, novel androgen receptor (AR) targeting strategies, and cell surface protein-directed therapies.
Purpose of the Study:
- To review current and emerging therapeutic strategies for metastatic prostate cancer.
- To highlight the role of PARP inhibitors, AR pathway inhibitors, and cell surface protein-targeting agents.
Main Methods:
- Review of current literature and clinical trial data on advanced prostate cancer treatments.
- Discussion of specific therapeutic classes: PARP inhibitors, AR pathway inhibitors, radioligand therapies, bispecific T cell engagers, and antibody-drug conjugates.
Main Results:
- Combination therapy with PARP inhibitors (PARPi) and AR pathway inhibitors (ARPI) is favored for homologous recombination repair (HRR)-mutated metastatic castration-resistant prostate cancer (CRPC) patients who can tolerate it.
- PARPi monotherapy benefits patients with BRCA1 or BRCA2 mutations unable to tolerate combination treatment.
- New AR-directed therapies (ligand degraders, CYP11A1 inhibitors) show promise for metastatic CRPC, potentially benefiting earlier disease stages.
- Radioligand therapy (177Lu-PSMA-617) is effective for PSMA-avid metastatic CRPC post-ARPI and chemotherapy.
- Bispecific T-cell engagers and novel radioligand therapies targeting cell surface proteins show promising survival benefits.
Conclusions:
- Personalized medicine, utilizing biomarker-based therapies, is transforming advanced prostate cancer management.
- PARP inhibitors and AR-directed therapies represent significant progress, with combination strategies and monotherapy offering tailored options.
- Targeting cell surface proteins via radioligand therapy and bispecific T-cell engagers presents a promising frontier for improving patient survival.
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