Apalutamide: Indications and Evidence in Advanced Prostate Cancer

Indications

• The NCCN guideline recommends apalutamide for two advanced‑prostate‑cancer populations: (1) non‑metastatic castration‑resistant prostate cancer (nmCRPC) with a PSA doubling time ≤ 10 months, and (2) metastatic castration‑sensitive prostate cancer (mCSPP), both in combination with continuous androgen‑deprivation therapy (ADT). [1][2]

Efficacy in Non‑Metastatic Castration‑Resistant Prostate Cancer (nmCRPC)

• The FDA approved apalutamide for nmCRPC on 14 February 2018 based on the phase III SPARTAN trial, which demonstrated a 24‑month improvement in metastasis‑free survival (HR 0.28, p < 0.001). This high‑level evidence supports a Category 1 (preferred) recommendation. 1

• NCCN classifies apalutamide 240 mg daily as a Category 1 (preferred) option for patients with nmCRPC who have a PSA doubling time ≤ 10 months, no detectable metastases on conventional imaging, and castrate testosterone levels (<50 ng/dL). 1

Efficacy in Metastatic Castration‑Sensitive Prostate Cancer (mCSPC)

• The FDA approved apalutamide for mCSPC on 17 September 2019 based on the phase III TITAN trial, which enrolled 1,052 men with de novo or recurrent metastatic disease. 2

• NCCN (derived from TITAN data) recommends apalutamide 240 mg daily plus ADT for both high‑ and low‑volume mCSPC, including patients with de novo metastases and those previously treated with radical prostatectomy or radiotherapy. 2

• In TITAN, 62.7 % of participants had high‑volume disease (defined as visceral metastases with ≥1 bone lesion, or ≥4 bone lesions with at least one outside the spine/pelvis); the survival benefit was consistent across high‑ and low‑volume subgroups. 2

• Approximately 10.7 % of TITAN participants had received prior docetaxel; apalutamide showed a trend toward benefit in this subgroup, but the difference was not statistically significant and warrants longer follow‑up. 2

Safety Monitoring and Adverse Events

• NCCN advises baseline and periodic monitoring of testosterone, lactate dehydrogenase (LDH), hemoglobin, alkaline phosphatase, and thyroid function, together with PSA every 3–6 months and conventional imaging every 6–12 months while on apalutamide. (Monitoring recommendation derived from NCCN guidance.)

• The SPARTAN trial reported higher incidences of several adverse events with apalutamide versus placebo: rash (23.8 % vs 5.5 %), fractures (11 % vs 6.5 %), hypothyroidism (8 % vs 2 %), and falls (15.6 % vs 9.0 %). These safety signals are incorporated into NCCN monitoring recommendations. 1

• Concomitant low‑dose prednisone may be used with apalutamide, but it is not mandatory according to NCCN guidance. 1

Androgen Receptor Inhibitors in Prostate Cancer Treatment

Introduction to Androgen Receptor Inhibitors

• The National Comprehensive Cancer Network recommends androgen receptor inhibitors, specifically darolutamide, apalutamide, and enzalutamide, as Category 1, preferred treatment options for non-metastatic castration-resistant prostate cancer (nmCRPC) when PSA doubling time is ≤10 months, with significant improvements in metastasis-free survival and overall survival 3, 4, 5

Clinical Context and Terminology

• Androgen receptor (AR) inhibitors work by competitively inhibiting androgen binding to the AR, blocking AR nuclear translocation, and preventing AR-mediated transcription, with darolutamide, apalutamide, and enzalutamide being established therapeutic agents 3, 6

Non-Metastatic Castration-Resistant Prostate Cancer (nmCRPC)

• The American Urological Association and the National Comprehensive Cancer Network suggest offering AR inhibitor therapy when PSA doubling time (PSADT) is ≤10 months, with no visible metastatic disease on conventional imaging, and castrate testosterone levels maintained (<50 ng/dL) 3, 6, 7, 8
• Darolutamide 600 mg twice daily with food has shown metastasis-free survival of 40.4 vs 18.4 months (HR 0.41; P<0.001) and 3-year overall survival of 83% vs 77% (HR 0.69; P=0.003), with a favorable safety profile 3, 4, 5
• Apalutamide 240 mg daily has demonstrated metastasis-free survival of 40.5 vs 16.2 months (HR 0.28; P<0.001) and final overall survival of 73.9 vs 59.9 months (HR 0.78; P=0.016), with monitoring required for rash, fractures, hypothyroidism, and falls 3, 4, 6, 9
• Enzalutamide 160 mg daily has shown overall survival of 67.0 vs 56.3 months (HR 0.73; P=0.001), with higher risk of hypertension, major adverse cardiovascular events, mental impairment, and seizures 3, 4

Metastatic Castration-Sensitive Prostate Cancer

• AR inhibitors are also FDA-approved for metastatic castration-sensitive disease in combination with ADT, with apalutamide plus ADT improving 24-month overall survival (82.4% vs 73.5%; HR 0.67, P=0.005) and radiographic progression-free survival at 24 months (68.2% vs 47.5%; HR 0.48, P<0.001) 8, 10

Monitoring Requirements

• During AR inhibitor therapy, serial PSA every 3-6 months, conventional imaging every 6-12 months, and baseline and periodic monitoring of testosterone, LDH, hemoglobin, alkaline phosphatase, and thyroid function are recommended 3, 6, 7
• Blood pressure monitoring is also necessary for all agents 3, 6, 4

Common Pitfalls to Avoid

• The National Comprehensive Cancer Network advises against using AR inhibitors without confirming castrate testosterone levels (<50 ng/dL), calculating PSADT to identify high-risk patients (≤10 months), and continuing concurrent ADT (LHRH agonist/antagonist) 3, 8