TITAN Trial in Metastatic Castration-Sensitive Prostate Cancer
Primary Treatment Recommendation
For patients with metastatic castration-sensitive prostate cancer, apalutamide 240 mg daily plus androgen deprivation therapy (ADT) is a Category 1 treatment option that significantly improves both radiographic progression-free survival and overall survival. 1
Key Trial Results
The TITAN trial was a double-blind phase III study that randomized 1,052 patients with metastatic castration-sensitive prostate cancer to receive either apalutamide (240 mg/day) or placebo, both combined with ADT 1:
Primary Endpoints (Initial Analysis at 22.7 months median follow-up):
- Radiographic progression-free survival: 68.2% vs 47.5% at 24 months (HR 0.48; 95% CI 0.39-0.60; P<0.001) 1
- Overall survival: 82.4% vs 73.5% at 24 months (HR 0.67; 95% CI 0.51-0.89; P=0.005) 1
Final Analysis Results (44 months median follow-up):
- Median overall survival: Not reached vs 52.2 months (HR 0.65; 95% CI 0.53-0.79; P<0.001) 1
Patient Selection Criteria
Apalutamide plus ADT should be offered to the following patient populations 1:
- Newly diagnosed metastatic disease (de novo metastatic castration-sensitive prostate cancer) 1
- Relapsed metastatic disease after prior local therapy (radical prostatectomy or radiotherapy) 1
- All disease volumes (both high-volume and low-volume disease showed benefit) 1
- Patients stratified by Gleason score at diagnosis 1
Important Caveat for Prior Docetaxel Use:
The benefit in patients previously treated with docetaxel showed favorable trends for radiographic progression-free survival but was not statistically significant in subgroup analysis 1. However, only 10-11% of TITAN patients had prior docetaxel exposure, and longer follow-up data are needed to confirm benefits in this specific subgroup 1.
Dosing Regimen
- Apalutamide: 240 mg orally once daily 1
- ADT: Continuous LHRH agonist/antagonist or surgical castration 1
- Duration: Continue until disease progression or unacceptable toxicity 1
Safety Profile and Monitoring
Common Adverse Events (more frequent with apalutamide):
- Rash (more common than placebo) 1
- Hypothyroidism (requires monitoring) 1
- Ischemic heart disease (cardiovascular monitoring needed) 1
Critical Safety Points:
- Grade 3-4 adverse events were similar between treatment groups (approximately 24-26%) 1
- Health-related quality of life was maintained during treatment 1
- No unexpected adverse events were observed 1
FDA Approval Status
Apalutamide received FDA approval for metastatic castration-sensitive prostate cancer in September 2019 1.
Clinical Practice Integration
When to Use Apalutamide vs Other Options:
Apalutamide is one of three second-generation antiandrogens with proven survival benefit in metastatic castration-sensitive prostate cancer 1:
- Apalutamide (TITAN trial) - Category 1 recommendation 1
- Enzalutamide (ARCHES/ENZAMET trials) - Category 1 recommendation 1
- Abiraterone (LATITUDE/STAMPEDE trials) - Category 1 recommendation 1
Selection Considerations:
- All three agents show similar magnitude of benefit for overall survival 1
- Cost and patient-specific tolerability should guide selection among these options 1
- Apalutamide may have lower rates of fatigue, falls, and fractures compared to other agents 2
- Patients achieving deep PSA decline (≤0.2 ng/mL) at 3 months have longer preservation of quality of life 3
Common Pitfalls to Avoid
- Do not delay treatment waiting for symptoms to develop - early initiation with metastatic disease improves survival 1
- Do not use first-generation antiandrogens (bicalutamide, nilutamide, flutamide) as alternatives when second-generation agents are available, as they provide inferior survival outcomes 1
- Do not assume lack of benefit in older patients - the TITAN trial included patients across age ranges with consistent benefit 1
- Ensure castrate testosterone levels are maintained throughout treatment with ADT monitoring 1