Comparative Effectiveness of First‐Line Treatments for Castration‐Resistant Prostate Cancer: A Large‐Scale Retrospective Study in Japan - Hashizume - The Prostate - Wiley Online Library

(a) Time to treatment failure. The median time to treatment failure was longest in the ENZ group compared with ABI and DOC (ENZ vs. ABI vs. DOC: 25.0 vs. 21.0 vs. 10.0 months; p < 0.0001). The hazard ratio (HR) for ENZ vs. ABI was 0.841 (p < 0.0001), and for ABI vs. DOC was 0.558 (p < 0.0001). 
(b) Overall Survival in all patients with CRPC. The median overall survival was 71 months in both the ENZ and ABI groups, and 60 months in the DOC group. ENZ vs. ABI showed a statistically significant difference (HR: 0.903; p = 0.003), as did ABI vs. DOC (HR: 0.718; p < 0.0001). ABI, abiraterone acetate; DOC, docetaxel; ENZ, enzlutamide. [Color figure can be viewed at wileyonlinelibrary.com]
Major Japanese Study Provides New Insights on First-Line CRPC Treatment: Enzalutamide vs. Abiraterone vs. Docetaxel

What This Means for You: New evidence helps guide treatment decisions for castration-resistant prostate cancer

By: Medical Editor, IPCSG Newsletter

A groundbreaking new study from Japan, the largest of its kind to date, is providing important insights into which treatments work best as first-line therapy for castration-resistant prostate cancer (CRPC). The research, published in The Prostate journal in July 2025, analyzed real-world data from nearly 19,000 Japanese patients—making it one of the most comprehensive studies ever conducted on this critical question.

Key Findings That Matter to Patients

The Japanese researchers compared three common first-line treatments for CRPC:

  • Enzalutamide (Xtandi) - 10,466 patients
  • Abiraterone acetate (Zytiga) - 6,841 patients
  • Docetaxel (Taxotere) - 1,617 patients

The Bottom Line: Enzalutamide was associated with prolonged overall survival compared to abiraterone (HR: 0.903, p < 0.003), and both enzalutamide and abiraterone significantly outperformed docetaxel in terms of survival and time to treatment failure.

What Makes This Study Special

Unlike clinical trials that often have strict eligibility criteria, this study examined "real-world" outcomes using data from actual clinical practice across Japan's healthcare system. The study utilized a database of Japanese DPC hospitals, comprising approximately 25.6% coverage, analyzing 410,000 patients with prostate cancer over nearly 15 years.

Treatment Outcomes: The Numbers

Time to Treatment Failure:

  • Enzalutamide: 25.0 months
  • Abiraterone: 21.0 months
  • Docetaxel: 10.0 months

Overall Survival:

  • Enzalutamide: 71 months
  • Abiraterone: 71 months
  • Docetaxel: 60 months

Important Finding for Bone Metastases: In patients with bone metastases specifically, the study found no significant difference between enzalutamide and abiraterone, suggesting both are equally effective in this population.

Sequential Therapy: An Important Strategy

The study also examined what happens when patients receive one hormonal therapy followed by another. Sequential therapy starting with abiraterone followed by enzalutamide did not result in a significant difference in time to treatment failure but was associated with a slight improvement in overall survival.

Key Finding: Starting with abiraterone and then switching to enzalutamide appeared to provide better overall survival than the reverse sequence, consistent with findings from other countries.

Why This Research Matters

Dr. Takashi Kawahara, the study's lead author from Yokohama City University, noted that Japanese patients have high hormone levels and higher survival rates than Caucasian patients, making this population-specific data particularly valuable for treatment decisions.

The research addresses a critical gap because, as the authors note, previous studies comparing these treatments directly have been limited, and large-scale Japanese data on the choice of first-line treatment for CRPC are lacking.

Recent Global Developments: What's New in 2024-2025

Groundbreaking FDA Approval for Earlier Pluvicto Use

In a major development for CRPC treatment, on March 28, 2025, the U.S. Food and Drug Administration (FDA) approved an expanded use of Pluvicto for patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously been treated with an androgen receptor pathway inhibitor (ARPI) and are considered appropriate candidates to delay chemotherapy.

This approval was based on the PSMAfore trial, which showed Pluvicto significantly reduced risk of progression or death by 59% and more than doubled median radiographic progression-free survival (rPFS) vs. change in ARPI.

What This Means: Patients can now access Pluvicto radioligand therapy earlier in their treatment journey, potentially before needing chemotherapy.

Meta-Analysis Confirms Treatment Preferences

A major meta-analysis published in February 2025 in Frontiers in Oncology analyzed real-world data and found that across all analyses, enzalutamide demonstrated a statistically significant improvement in OS compared with abiraterone, supporting the Japanese study's findings.

Long-Term Follow-Up Data

Recent 5-year follow-up data from the ARCHES trial presented at ASCO 2025 showed enzalutamide plus ADT was associated with a 66% probability of survival at 5 years and a 30% reduction in the risk of death compared to placebo plus ADT.

Treatment Selection: Personalized Approaches

Current evidence suggests that treatment selection should consider several factors:

For Most Patients: Enzalutamide may have a slight edge over abiraterone based on the Japanese study and recent meta-analyses.

For Patients with Bone Metastases: Both enzalutamide and abiraterone appear equally effective.

For Patients Considering Sequence: Starting with abiraterone followed by enzalutamide may provide optimal sequential therapy benefits.

For Patients Seeking to Delay Chemotherapy: Pluvicto is now an FDA-approved option after hormonal therapy progression.

The Bigger Picture: Treatment Evolution

As Dr. Alicia Morgans from Dana-Farber Cancer Institute noted in ZERO's 2024-2025 Advanced Prostate Cancer Newsletter, "In 2025, we are likely to see data from trials offering completely novel approaches to treatment, and doctors and patients will have more choices than ever before".

The treatment landscape continues to expand with:

  • Earlier use of radioligand therapies
  • Improved understanding of treatment sequencing
  • Personalized approaches based on genetic testing
  • Quality of life considerations

What Patients Should Discuss with Their Doctors

  1. Individual Risk Factors: Your specific disease characteristics, including presence of bone metastases
  2. Treatment Goals: Balancing effectiveness with quality of life
  3. Sequencing Strategy: Planning for potential second-line treatments
  4. Clinical Trial Opportunities: Access to newer therapies
  5. PSMA PET Imaging: Eligibility for radioligand therapies

Looking Ahead

The Japanese study's authors concluded that despite the limitations in the data set, the findings support the use of ABI-ENZ sequential therapy, which may provide additional clinical benefits in terms of overall survival.

As research continues, patients can expect:

  • More personalized treatment selection
  • Earlier intervention with effective therapies
  • Better understanding of optimal treatment sequences
  • Continued improvements in overall survival

Remember: This research provides valuable guidance, but treatment decisions should always be individualized based on your specific situation, preferences, and discussions with your healthcare team.

Sources and References

  1. Hashizume, A., Kawahara, T., Ito, Y., et al. (2025). Comparative Effectiveness of First‐Line Treatments for Castration‐Resistant Prostate Cancer: A Large‐Scale Retrospective Study in Japan. The Prostate, 1-7. https://doi.org/10.1002/pros.70005
  2. Aprikian, A., Bahl, A., Omlin, A., et al. (2025). Meta-analysis to evaluate the comparative effectiveness of enzalutamide and abiraterone acetate for first-line treatment of metastatic castration-resistant prostate cancer in real-world settings. Frontiers in Oncology, 15:1491314. https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1491314/full
  3. Morris, M.J., Castellano, D., Herrmann, K., et al. (2024). 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. The Lancet, 404(10459):1227-1239. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)01653-2/abstract
  4. Novartis. (2025, March 28). FDA approves Novartis radioligand therapy Pluvicto® for earlier use before chemotherapy in PSMA-positive metastatic castration-resistant prostate cancer. https://www.novartis.com/news/media-releases/fda-approves-novartis-radioligand-therapy-pluvicto-earlier-use-chemotherapy-psma-positive-metastatic-castration-resistant-prostate-cancer
  5. Armstrong, A.J., Azad, A.A., Iguchi, T., et al. (2025). ARCHES: 5-Year Follow-up Overall Survival Analysis of Enzalutamide plus Androgen-Deprivation Therapy in Patients with Metastatic Hormone-Sensitive Prostate Cancer. Presented at ASCO 2025. https://www.urotoday.com/conference-highlights/asco-2025/asco-2025-prostate-cancer/161075-asco-2025-arches-5-year-follow-up-overall-survival-os-analysis-of-enzalutamide-enza-plus-androgen-deprivation-therapy-adt-in-patients-pts-with-metastatic-hormone-sensitive-prostate-cancer-mhspc.html
  6. ZERO Prostate Cancer. (2025). Advanced Prostate Cancer Newsletter: Winter 2024/2025. https://zerocancer.org/newsletters/advanced-prostate-cancer/2024-2025
  7. OncoLive. (2025, April 11). PSMAfore Data Drive Expanded Approval of Lutetium Lu 177 Vipivotide Tetraxetan in mCRPC. https://www.onclive.com/view/psmafore-data-drive-expanded-approval-of-lutetium-lu-177-vipivotide-tetraxetan-in-mcrpc

This newsletter story is for educational purposes only and should not replace medical advice. Always consult with your healthcare team about treatment decisions.

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Comparative Effectiveness of First‐Line Treatments for Castration‐Resistant Prostate Cancer: A Large‐Scale Retrospective Study in Japan - Hashizume - The Prostate - Wiley Online Library

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