What is the primary aim of a Phase 1, open-label, multicenter study of a new treatment for metastatic castration-resistant prostate cancer (mCRPC)?

Primary Aim of Phase 1 Studies in Metastatic Castration-Resistant Prostate Cancer

The primary aim of a Phase 1, open-label, multicenter study in mCRPC is to determine the maximum tolerated dose (MTD) and establish the safety profile of the investigational treatment, while obtaining preliminary evidence of antitumor activity. 1

Core Objectives of Phase 1 Trials in mCRPC

Safety and Dose-Finding (Primary Focus)

• Establish the MTD through systematic dose escalation, typically starting at lower doses (e.g., 30-600 mg/d range) and escalating until dose-limiting toxicities are identified 2
• Characterize the safety profile by monitoring adverse events at each dose level, with particular attention to dose-dependent toxicities 2
• Define the recommended phase 2 dose (RP2D) based on tolerability and pharmacokinetic data 2

Preliminary Efficacy Assessment (Secondary Focus)

While not the primary endpoint, Phase 1 studies in mCRPC routinely assess:

• PSA response rates as an early signal of antitumor activity, though PSA outcomes must be interpreted within the context of the drug's mechanism of action 1
• Radiographic response using baseline and follow-up imaging to detect tumor shrinkage or stabilization 1
• Time to PSA progression and radiographic progression as exploratory endpoints 2

Critical Design Elements per PCWG3 Guidelines

Baseline Characterization

All Phase 1 mCRPC studies should include comprehensive baseline assessments 1:

• Hematologic, hepatic, and renal function (hemoglobin, alkaline phosphatase, albumin, lactate dehydrogenase as established prognostic factors)
• Testosterone levels (castrate defined as ≤50 ng/dL)
• Tumor biopsy of metastatic sites for histology and biomarker assessment to enable biologic characterization 1
• Blood-based diagnostics including circulating tumor cells (CTCs), circulating nucleic acids, or host factors 1

Patient Population Stratification

Phase 1 studies should clearly define and stratify patients by prior treatment exposure 1:

• No prior docetaxel/no prior novel hormone therapy
• Prior novel hormone therapy/no prior docetaxel
• Prior docetaxel/no prior novel hormone therapy
• Prior docetaxel/prior novel hormone therapy

This stratification is critical because cross-resistance between abiraterone and enzalutamide is well-documented, and sequencing matters significantly for patient outcomes 1.

Disease Characterization Requirements

Document the type of progression at trial entry 1:

• PSA-only progression
• Radiographic progression by site (bone, nodal, visceral)
• Whether progression represents growth of existing lesions, new lesions, or both
• Whether progression occurs in single versus multiple organ sites

Record location of disease separately 1:

• Nodal disease: pelvic versus extrapelvic
• Visceral disease: lung/liver/adrenal/CNS (each has distinct prognostic implications)
• Monitor up to five individual lesions per site of spread

Patient-Reported Outcomes Integration

Phase 1 studies should incorporate validated PRO instruments 1:

• Pain intensity and interference measures
• Physical functioning assessments
• Patient-reported adverse events using NCI's PRO-CTCAE
• These data are essential for understanding quality of life impacts even in early-phase trials

Common Pitfalls to Avoid

Inadequate Long-Term Safety Monitoring

Phase 1 studies must plan for extended follow-up beyond initial dose-finding, as some patients may show durable responses requiring years of treatment 2. The enzalutamide Phase 1-2 study demonstrated that safety profiles remain consistent over time, but long-term tolerability data (>4 years) are crucial for drugs intended for chronic use 2.

Insufficient Molecular Characterization

Failure to obtain tumor biopsies at progression represents a missed opportunity 1. The PCWG3 guidelines explicitly recommend rebiopsy of progressing metastatic sites to understand resistance mechanisms and guide future drug development 1.

Ignoring Treatment Sequencing Context

Phase 1 trials must account for the evolving treatment landscape where patients increasingly receive novel hormone therapies (abiraterone, enzalutamide, apalutamide, darolutamide) in earlier disease states 1. This prior exposure fundamentally alters the biology of mCRPC and affects response to subsequent therapies 1.

Biomarker-Driven Approach

Modern Phase 1 studies should incorporate molecular profiling 3:

• Homologous recombination repair gene defects (BRCA1/2)
• Androgen receptor splice variant 7 (AR-V7) status
• PTEN deletion status
• Mismatch repair alterations
• Evidence of neuroendocrine differentiation 4

These biomarkers increasingly guide therapeutic decision-making and should be integrated into early-phase trial design to enable future precision medicine approaches 3.