Drugs in Phase III Trials for Metastatic Castration-Resistant Prostate Cancer
Based on the most recent guideline evidence, the drugs actively in Phase III trials for mCRPC as of 2015 included custirsen (in combination with docetaxel and cabazitaxel), cabozantinib, and PROSTVAC, though several of these programs have since been terminated or completed. 1
Active Phase III Trials (Historical Context from 2015 Guidelines)
Custirsen Combinations
- Custirsen + docetaxel/prednisone: A completed but unpublished Phase III trial (NCT01188187) was evaluating this combination, adding a novel mechanism of action to the docetaxel backbone. 1
- Custirsen + cabazitaxel/prednisone: A Phase III trial (NCT01578655) was recently activated at the time of guideline publication, comparing cabazitaxel plus prednisone with or without custirsen. 1
Cabozantinib
- Cabozantinib is a MET and VEGFR2 oral tyrosine kinase inhibitor that showed promising anti-tumor activity in Phase II trials, particularly in patients with bone metastases. 1
- Two Phase III trials were ongoing in the post-docetaxel setting: NCT01605227 and NCT01522443. 1
Orteronel (Program Terminated)
- Orteronel, a CYP17A inhibitor (specifically a 17,20-lyase inhibitor), was being tested in a Phase III trial (NCT01193244) comparing orteronel plus prednisone to placebo plus prednisone. 1
- Critical caveat: As of June 19,2014, the development program for orteronel was voluntarily terminated after Phase III results showed the drug failed to extend overall survival. 1
PROSTVAC Immunotherapy
- PROSTVAC was being tested in a Phase III study (NCT01322490) in asymptomatic, chemotherapy-naïve men with mCRPC, randomizing participants to PROSTVAC with or without GM-CSF versus placebo. 1
Current Landscape (2023-2025 Updates)
Breakthrough Therapies Now Established
While the question asks about Phase III trials, it's important to note that several agents have completed Phase III trials and are now standard of care:
- Lutetium-177 PSMA-617: The VISION trial demonstrated dramatic survival benefits (HR 0.62 for OS, P < 0.001) in heavily pretreated mCRPC patients. 2
- Olaparib: The PROfound trial showed significant survival benefit (HR 0.69, P = 0.0175) in men with BRCA1/2 or ATM alterations. 2
Important Clinical Context
- The AUA guideline emphasizes that the impact on survival from individual agents in mCRPC remains modest, measured only in months, highlighting the need for continued investigation of novel agents and rational combinations. 1
- A major deficiency in prostate cancer drug development has been the lack of predictive biomarkers to personalize therapy, making clinical trial participation crucial. 1
Common Pitfalls
- Orteronel failure: Clinicians should be aware that not all promising Phase II agents succeed in Phase III trials, as demonstrated by orteronel's failure to extend OS despite being a CYP17A inhibitor. 1
- Sequencing uncertainty: The optimal sequence of approved treatments remains undefined, requiring prospective studies to guide proper use considering efficacy and cost-effectiveness. 1
- Cross-resistance concerns: Understanding mechanisms of resistance to current therapies is critical for future treatment development and sequencing decisions. 1