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[Preprint]. 2025 Apr 16:2025.04.15.25325837.
doi: 10.1101/2025.04.15.25325837.

Systemic treatment options for metastatic castration resistant prostate cancer: A living systematic review

Syed Arsalan Ahmed Naqvi  1 , Muhammad Umair Anjum  1 , Arifa Bibi  2 , Muhammad Ali Khan  1 , Kaneez Zahra Rubab Khakwani  3 , Huan He  4 , Manal Imran  5 , Syeda Zainab Kazmi  5 , Ammad Raina  6 , Ewan K Cobran  7 , R Bryan Rumble  8 , Thomas K Oliver  8 , Neeraj Agarwal  9 , Yousef Zakharia  1 , Mary-Ellen Taplin  10 , Oliver Sartor  11 , Parminder Singh  1 , Jacob J Orme  11 , Daniel S Childs  11 , Rahul A Parikh  12 , Rohan Garje  13 , Mohammad Hassan Murad  14 , Alan H Bryce  15 , Irbaz Bin Riaz  1
Affiliations

Systemic treatment options for metastatic castration resistant prostate cancer: A living systematic review

Syed Arsalan Ahmed Naqvi et al. medRxiv. .

Abstract

Background: Optimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting.

Purpose: To synthesize and appraise evidence on systemic therapy for mCRPC patients stratified by prior therapy and HRR alterations informing a clinical practice guideline.

Data sources: MEDLINE and EMBASE (inception to 5 March 2025) using living search.

Study selection: Randomized clinical trials assessing systemic therapy in mCRPC.

Data extraction: Primary outcomes assessed were progression free survival (PFS) and overall survival (OS).

Data synthesis: This report of the living systematic review (LSR) includes 143 trials with 17,523 patients (59 phase III/IV trials, 8,941 patients; 84 phase II, 8,582 patients). In the setting of prior androgen deprivation therapy (ADT) alone or ADT+docetaxel, treatment benefit was observed with poly (ADP-ribose) polymerase inhibitors (PARPi) in combination with androgen receptor pathway inhibitors (ARPI) for BRCA+ subgroup. In the setting of prior ADT+ARPI or ADT+ARPI+docetaxel, treatment benefit was observed with PARPi monotherapy for BRCA+ subgroup. Treatment benefit with PARPi may be observed for select non-BRCA homologous recombination repair (HRR) alterations (CDK12, PALB2). Treatment benefit was observed with abiraterone, enzalutamide, cabazitaxel, docetaxel (if no prior docetaxel), and Lu177 (if PSMA+) for patients without HRR alterations.

Limitations: Study-level data and indirectness in evidence.

Conclusion: Findings from the current LSR suggest that optimal treatment for mCRPC should be individualized based on prior therapy and HRR alterations. Current evidence favors PARPi alone (ARPI exposed) or in combination with ARPI (ARPI naïve) for patients with BRCA alterations, while ARPI alone, chemotherapy, and Lu177 remain potential options for patients without HRR alterations.

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Conflict of interest statement

Conflicts of Interest: Syed Arsalan Ahmed Naqvi, Muhammad Umair Anjum, Arifa Bibi, Muhammad Ali Khan, Kaneez Zahra Rubab Khakwani, Huan He, Manal Imran, Syeda Zainab Kazmi, Ammad Raina, Ewan K. Cobran, R. Bryan Rumble, Thomas K. Oliver, Jacob J. Orme, Muhammad Hassan Murad, and Irbaz Bin Riaz do not have any relevant competing interests to disclose. Neeraj Agarwal (NA): NA received honorarium before May 2021 and during his lifetime for consulting to Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. He has also received research funding during his lifetime (to NA’s institution) from Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Meyers Squibb, Calithera, Celldex, Clovis, CRISPR Therapeutics, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Yousef Zakharia (YZ): YZ has received honoraria for data safety monitoring board membership from Janssen Research and Development. He has served as a consultant or advisor to Roche/Genentech, Eisai, Amgen, Castle Biosciences, Novartis, Exelixis, Pfizer, Cardinal Health, Bayer, Janssen, TTC Oncology, Clovis Oncology, EMD Serono, Seagen, Bristol Myers Squibb/Medarex, Myovant Sciences, Genzyme, Gilead Sciences, AstraZeneca and Array BioPharma. He has received research funding to his institution from Pfizer, Exelixis, and Eisai. His travel, accommodations, and expenses have been supported by Newlink Genetics. Mary Ellen Taplin (MET): MET has served on the advisory boards for Astellas, Novartis, Lakena, Flare, Pfizer, J&J, and AstraZeneca. Oliver Sartor (OS): OS has received grants/contracts from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, In Vitae, Janssen, Lantheus, Merck, Novartis, Sanofi, and Point Biopharma. He has also received consulting fees from Advanced Accelerator Applications, Amgen, ART Bioscience, Astellas Pharma, AstraZeneca, Bayer, Clarity Pharmaceuticals, EMD Serono, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, MacroGenics, Novartis, Pfizer, Point Biopharma, Ratio, Sanofi, Telix Pharmaceuticals, and TeneoBio. Additionally, he has participated on a data safety monitoring board/advisory board for Pfizer, Merck, Janssen, AAA, Novartis, and AstraZeneca; received support for attending meeting and/or travel from Bayer, Lantheus, and Sanofi; and has stock/stock options in AbbVie, Cardinal Health, Clarity Pharmaceuticals, Convergent, Eli Lilly, Abbot, Ratio, United Health Group, and Telix. Parminder Singh (PS): PS has served on the advisory boards for Aveo Pharmaceuticals, Bayer Healthcare Pharmaceuticals, EMD Serono Inc, and Janssen Research & Development, LLC. Daniel S. Childs (DSC): DSC has received honoraria from Targeted Oncology, IntrinsiQ, MJH Life Sciences, and the International Centers for Precision Oncology Foundation. He has served as a consultant or advisor to Janssen Biotech (institution) and Novartis (institution) and received research funding to his institution from Janssen Biotech. His travel, accommodations, and expenses have been supported by the Prostate Cancer Foundation. Rahul A. Parikh (RP): RP has stock and other ownership interests in IBRX. He has also received a patent on DNA repair pathways in cancer but does not receive any royalty from this. Rohan Garje (RG): RG has received research funding to his institution from Endocyte/Advanced Accelerator Applications, Pfizer, Amgen, Immunomedics, Xencor, Exelixis, and Janssen Oncology. Alan Haruo Bryce (AHB): AHB has received grants from Janssen and funding to his institution from Janssen, AstraZeneca, and Gilead. Additionally, he has received personal fees from AstraZeneca, Merck, Bayer, Elsevier, Fallon Medica, Horizon CME, PRIME Education, MJH Life Sciences, and Novartis outside the submitted work. He also holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Registration: https://osf.io/46tjm

Figures

Figure 1.
Figure 1.
PRISMA flowchart outlining the study selection process
See this image and copyright information in PMC

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