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Novel Therapies in Metastatic Castration-Resistant Prostate Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 1 August 2026 | Viewed by 4971

Special Issue Editor


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Guest Editor
Department of Pharmaceutical Sciences, Washington State University Spokane, Spokane, DC, USA
Interests: prostate cancer; human ovarian cancer; fatty acid receptors

Special Issue Information

Dear Colleagues,

Novel therapies in metastatic castration-resistant prostate cancer (mCRPC) offer significant improvement in the treatment of this aggressive form of prostate cancer. These therapies aim to address the challenges posed by tumors that have become resistant to standard hormone therapy.  Traditionally, mCRPC was treated with chemotherapy and hormone therapies; however, the disease often progressed despite these interventions. Recently, several novel therapies have emerged.

  1. Signal transduction inhibitors: Drugs are under development to target novel signal transduction pathways important for prostate cancer cell proliferation, survival, and metastasis.
  2. Targeted therapies: Progress has been made in directly targeting drugs to prostate cancer cells, for example, via PSMA.
  3. Immunotherapy: Immune checkpoint inhibitors have shown promise in activating the body's immune system to fight prostate cancer cells.
  4. Radiopharmaceuticals: Radioactive agents like radium-223 selectively target bone metastases, improving patient quality of life and survival.
  5. PARP inhibitors: Drugs have demonstrated effectiveness in treating mCRPC patients with certain genetic mutations.
  6. Biomarker-based approaches: Precision medicine techniques, such as genomic profiling, help identify specific genetic alterations in tumors, allowing for tailored treatment plans.

Novel therapies in metastatic castration-resistant prostate cancer represent a promising frontier in oncology, offering new hope and improved outcomes for patients who were previously faced with limited treatment options. Ongoing research and advancements in personalized medicine continue to shape the landscape of mCRPC treatment.

Dr. Kathryn E. Meier
Guest Editor

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Keywords

  • signal transduction inhibitors
  • targeted therapies
  • immunotherapy
  • radiopharmaceuticals
  • PARP inhibitors
  • biomarker-based approaches

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Published Papers (2 papers)

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Research

19 pages, 3513 KB  
Article
PARP Inhibitors Combined with Abiraterone Overcome Resistance in Metastatic Castration-Resistant Prostate Cancer Independently of Androgen Receptor
by Hamza Mallah, Sina Soultani, Zania Diabasana, Véronique Lindner, Philippe Barthélémy, Ysia Idoux-Gillet and Thierry Massfelder
Cancers 2026, 18(4), 560; https://doi.org/10.3390/cancers18040560 - 9 Feb 2026
Viewed by 845
Abstract
Background: PC is the second most common malignancy in men, and progression to metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) remains incurable. Current treatments for mCRPC include chemotherapy, immunotherapy, radiopharmaceuticals, and second-line androgen receptor signaling inhibitors (ARSIs) such as Abiraterone. [...] Read more.
Background: PC is the second most common malignancy in men, and progression to metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) remains incurable. Current treatments for mCRPC include chemotherapy, immunotherapy, radiopharmaceuticals, and second-line androgen receptor signaling inhibitors (ARSIs) such as Abiraterone. PARP inhibitors (PARPis) have recently shown clinical benefits in tumors with homologous recombination repair (HRR) deficiencies, particularly BRCA1/2 mutations. Combining PARPi with ARSIs has improved progression-free (PFS) and overall survival (OS), especially in ARSI-naïve patients, but limited data exist for resistant disease. Objectives: This work focuses on intrinsically hormone-insensitive, AR-negative, BRCA-wildtype models, representing a clinically distinct population with limited therapeutic options. We thus investigated the therapeutic potential of combining Abiraterone with PARPis (Niraparib or Olaparib) in Abiraterone-resistant prostate cancer. Methods: Resistant PC3 and DU145 cell lines were analyzed using 2D and 3D cultures and cell-derived xenograft (CDX) mouse models. Results: Cytotoxicity assays revealed significantly reduced cell viability with combination therapy compared to single agents. These findings were supported by RT-qPCR, Western blot, and immunofluorescence analyses of xenograft tumors, demonstrating enhanced antitumor activity with the combination. Conclusions and significance: Overall, the results indicate that maintaining Abiraterone treatment in combination with PARPis after resistance develops provides superior therapeutic efficacy compared to PARP inhibition alone, offering a promising strategy for managing Abiraterone-resistant prostate cancer. Combining Abiraterone with PARPis enhances therapeutic efficacy and overcomes the acquired insensitivity in mCRPC with BRCA1/2 or HRR mutations. These results support continued use of PARPis with Abiraterone to improve clinical outcomes. Full article
(This article belongs to the Special Issue Novel Therapies in Metastatic Castration-Resistant Prostate Cancer)
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16 pages, 2560 KB  
Article
Synergistic Activity of DNA Damage Response Inhibitors in Combination with Radium-223 in Prostate Cancer
by Victoria L. Dunne, Timothy C. Wright, Francisco D. C. Guerra Liberal, Joe M. O’Sullivan and Kevin M. Prise
Cancers 2024, 16(8), 1510; https://doi.org/10.3390/cancers16081510 - 15 Apr 2024
Cited by 6 | Viewed by 3246
Abstract
Radium-223 (223Ra) and Lutetium-177-labelled-PSMA-617 (177Lu-PSMA) are currently the only radiopharmaceutical treatments to prolong survival for patients with metastatic-castration-resistant prostate cancer (mCRPC); however, mCRPC remains an aggressive disease. Recent clinical evidence suggests patients with mutations in DNA repair genes associated [...] Read more.
Radium-223 (223Ra) and Lutetium-177-labelled-PSMA-617 (177Lu-PSMA) are currently the only radiopharmaceutical treatments to prolong survival for patients with metastatic-castration-resistant prostate cancer (mCRPC); however, mCRPC remains an aggressive disease. Recent clinical evidence suggests patients with mutations in DNA repair genes associated with homologous recombination have a greater clinical benefit from 223Ra. In this study, we aimed to determine the utility of combining DNA damage response (DDR) inhibitors to increase the therapeutic efficacy of X-rays, or 223Ra. Radiobiological responses were characterised by in vitro assessment of clonogenic survival, repair of double strand breaks, cell cycle distribution, and apoptosis via PARP-1 cleavage. Here, we show that DDR inhibitors increase the therapeutic efficacy of both radiation qualities examined, which is associated with greater levels of residual DNA damage. Co-treatment of ATM or PARP inhibition with 223Ra increased cell cycle arrest in the G2/M phase. In comparison, combined ATR inhibition and radiation qualities caused G2/M checkpoint abrogation. Additionally, greater levels of apoptosis were observed after the combination of DDR inhibitors with 223Ra. This study identified the ATR inhibitor as the most synergistic inhibitor for both radiation qualities, supporting further pre-clinical evaluation of DDR inhibitors in combination with 223Ra for the treatment of prostate cancer. Full article
(This article belongs to the Special Issue Novel Therapies in Metastatic Castration-Resistant Prostate Cancer)
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