How long after starting apalutamide (generic name) should Prostate-Specific Antigen (PSA) levels start to decline?

PSA Decline After Starting Apalutamide

PSA typically begins to decline within 3 months of starting apalutamide, with most patients achieving a deep PSA response (≥90% reduction or PSA ≤0.2 ng/ml) by this timepoint.

Timeline of PSA Response with Apalutamide

Recent evidence from the TITAN trial demonstrates the following pattern of PSA decline with apalutamide:

• By 3 months of treatment:

  • 59% of patients achieve ≥90% PSA reduction
  • 51% of patients achieve PSA ≤0.2 ng/ml 1
  • 23% of patients achieve PSA ≤0.02 ng/ml (ultralow PSA) 2

• The median time to achieving a ≥90% PSA reduction is approximately 3.1 months 3

• By the end of treatment:

  • 90% of patients achieve ≥50% PSA reduction
  • 73% of patients achieve ≥90% PSA reduction
  • 68% of patients achieve PSA ≤0.2 ng/ml 1

Clinical Significance of Early PSA Response

The depth and rapidity of PSA decline with apalutamide has important prognostic implications:

• Patients who achieve a deep PSA decline (≥90% or ≤0.2 ng/ml) by 3 months have:

  • Significantly longer overall survival (HR 0.35)
  • Improved radiographic progression-free survival (HR 0.44)
  • Longer time to PSA progression (HR 0.31)
  • Longer time to castration resistance (HR 0.38) 1

• Those achieving the deepest PSA decline (≤0.02 ng/ml) by 3 months have even better outcomes:

  • Radiographic progression-free survival: HR 0.28
  • Overall survival: HR 0.24
  • Time to castration resistance: HR 0.2
  • Time to PSA progression: HR 0.11 2

Monitoring Recommendations

The St. Gallen Advanced Prostate Cancer Consensus Conference emphasizes the importance of cautious interpretation of PSA values in the first 2-3 months after starting a new treatment 4. This is because:

1. PSA flare can occur with newer hormonal therapies, with significant PSA falls after initial rise
2. Education of patients and physicians about uncertainties in PSA interpretation is critical

For ongoing monitoring after starting apalutamide:

• PSA should be measured every 3-4 weeks initially
• Regular imaging (CT scans and bone scans) should be performed even in the absence of clinical indications 4

Comparison with Other Androgen Receptor Inhibitors

Real-world evidence suggests that apalutamide may produce a more rapid PSA response compared to enzalutamide:

• Median time to ≥90% PSA reduction: 3.1 months with apalutamide vs. 5.2 months with enzalutamide
• By 6 months, patients on apalutamide have a 56% greater likelihood of attaining ≥90% PSA reduction than those on enzalutamide 3

Clinical Implications

The early and deep PSA response seen with apalutamide is associated with:

• Improved survival outcomes
• Longer maintenance of health-related quality of life
• Better preservation of physical well-being 5

Potential Pitfalls in PSA Interpretation

1. PSA flare phenomenon: Some patients may experience an initial rise in PSA before seeing a decline. This should not be immediately interpreted as treatment failure.

2. Variability in response: While most patients show significant PSA decline by 3 months, individual responses may vary.

3. Discordant results: The panel from the St. Gallen consensus stressed that PSA changes should be interpreted alongside clinical findings, as discordant results (e.g., PSA rise with clinical improvement) can occur 4.

4. Concomitant medications: Medications like 5-alpha reductase inhibitors can affect PSA levels and should be considered when interpreting results.

In conclusion, clinicians should expect to see PSA decline within the first 3 months of apalutamide treatment, with the majority of patients achieving significant PSA reduction by this timepoint. Early and deep PSA response is associated with better clinical outcomes and should be monitored regularly throughout treatment.