What Prostate-Specific Antigen (PSA) level can a patient with recurrent high-volume metastatic prostate cancer expect in 4 weeks after starting Androgen Deprivation Therapy (ADT) and apalutamide (Erleada), given a PSA doubling from 0.1 to 0.2 in 30 days?

From the Guidelines

A patient with recurrent high-volume metastatic prostate cancer who starts ADT plus apalutamide can expect a significant PSA decline within 4 weeks of treatment initiation, likely dropping by 50-90% from the baseline value of 0.2 ng/mL, resulting in a PSA level potentially between 0.02-0.1 ng/mL. This expectation is based on the mechanism of action of the combination therapy, which blocks androgen signaling through complementary mechanisms - ADT reduces testosterone production while apalutamide blocks androgen receptors, preventing remaining androgens from stimulating cancer growth 1. The rapid PSA decline reflects the hormone-sensitive nature of the recurrent disease.

Key Considerations

• The TITAN trial demonstrated that apalutamide plus ADT is associated with significantly longer radiographic progression-free survival (rPFS) and overall survival (OS) compared with placebo plus ADT 1.
• The ENZAMET trial showed that enzalutamide plus ADT is associated with significantly longer PSA progression-free survival, clinical progression-free survival, and overall survival compared with ADT alone 1.
• Individual responses to treatment may vary based on tumor biology, disease burden, and prior treatments.

Monitoring and Follow-up

• Regular PSA monitoring should continue throughout treatment, with measurements typically every 1-3 months, as the pattern and magnitude of PSA decline correlate with treatment efficacy and prognosis.
• If the PSA fails to decline appropriately or rises during treatment, it may indicate developing resistance, necessitating treatment reassessment.

Calculation of PSADT

• The Prostate Specific Antigen Working Group guidelines recommend calculating PSADT using at least 3 PSA values obtained over 3 months with a minimum of 4 weeks between measurements 1.
• The guidelines also recommend reporting PSADT in months, but in advanced disease states, weeks may be used where it is the appropriate time metric.

From the FDA Drug Label

Apalutamide 240 mg daily in addition to ADT in patients with mCSPC (TITAN) reduced PSA to undetectable levels (<0.2 ng/mL) in 68% of patients compared to 32% of patients taking ADT alone. Apalutamide 240 mg daily in addition to ADT in patients with nmCRPC (SPARTAN) reduced PSA to undetectable levels (<0. 2 ng/mL) in 38% of patients compared to no patients (0%) taking ADT alone.

The patient's PSA level can be expected to decrease, as apalutamide in addition to ADT has been shown to reduce PSA to undetectable levels in a significant percentage of patients. However, the exact PSA level in 4 weeks cannot be determined from the provided information.

• The drug label does provide information on the percentage of patients who achieved undetectable PSA levels, but it does not provide a specific PSA level that a patient can expect in 4 weeks.
• The patient's initial PSA doubling from 0.1 to 0.2 in 30 days may not be indicative of the PSA level in 4 weeks, as the effect of apalutamide on PSA levels can vary between patients 2. It is important to note that the exposure-response relationship and time course of pharmacodynamic response for apalutamide have not been fully characterized, making it difficult to predict the exact PSA level in 4 weeks 2.

From the Research

PSA Level Expectation in 4 Weeks

Given the patient's PSA doubling from 0.1 to 0.2 in 30 days after starting Androgen Deprivation Therapy (ADT) and apalutamide, we can look at the studies to understand the potential PSA level in 4 weeks.

• The studies 3, 4 suggest that apalutamide plus ADT can produce rapid, deep, and durable PSA responses in patients with metastatic castration-sensitive prostate cancer.
• By 3 months, PSA decreased in most apalutamide-treated patients, and the median time to PSA nadir was 7.4 months 3.
• Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS, rPFS, time to PSA progression, and time to castration resistance 4.
• However, the exact PSA level in 4 weeks cannot be directly determined from these studies, as they report median times to PSA nadir or deep PSA decline, rather than specific PSA levels at 4 weeks.

Factors Influencing PSA Level

Several factors can influence the PSA level, including:

• The patient's initial PSA level and doubling time
• The effectiveness of the ADT and apalutamide treatment
• The presence of metastases and their volume
• The patient's overall health and any comorbidities

Study Findings

The studies 5, 6 report on the association between PSA responses and clinical outcomes in patients with metastatic hormone-sensitive prostate cancer.

• Darolutamide plus ADT and docetaxel led to deep and durable PSA responses in patients with high- or low-volume metastatic hormone-sensitive prostate cancer 5.
• Achievement of undetectable PSA (<0.2 ng/ml) was correlated with better clinical outcomes, including longer OS and time to PSA progression 5, 6.
• However, these studies do not provide specific guidance on the expected PSA level in 4 weeks for a patient with recurrent high-volume metastatic prostate cancer.

PSA Level in 4 Weeks

Based on the available evidence, it is difficult to predict the exact PSA level in 4 weeks for this patient. However, given the rapid PSA doubling time and the initiation of ADT and apalutamide, it is possible that the PSA level may continue to increase or stabilize in the short term.

• Further monitoring of the patient's PSA level and clinical status is necessary to determine the effectiveness of the treatment and adjust the treatment plan as needed.
• The patient's PSA level should be closely monitored, and adjustments to the treatment plan should be made based on the patient's response to therapy.