Apalutamide (Erleada) and enzalutamide (Xtandi) are second-generation androgen receptor pathway inhibitors (ARPIs) designed to treat prostate cancer. This disease is often driven by male hormones (androgens), which bind to receptors on cancer cells and promote their growth. These two drugs were developed to more potently block this signaling pathway compared to earlier treatments. While they share a fundamental purpose and a similar molecular target, their distinct chemical structures lead to important differences in clinical use and tolerability.
Shared Mechanism of Action
Both apalutamide and enzalutamide function by targeting the androgen receptor (AR) within prostate cancer cells, effectively shutting down the primary pathway that fuels tumor growth. Prostate cancer often relies on the AR to receive growth signals from circulating androgens. The core strategy of both drugs is to interfere with the function of this receptor.
They achieve this interference through a three-pronged molecular mechanism of action. First, both drugs competitively bind to the AR, preventing androgens from attaching and activating the receptor. Second, the binding of the drug inhibits the activated AR from moving, or translocating, into the cell’s nucleus. Finally, these drugs impair the AR’s ability to bind to DNA, which is necessary for it to trigger the transcription of genes that promote cancer cell survival and proliferation.
This shared, highly potent mechanism distinguishes them from first-generation anti-androgens, which were less effective at blocking all stages of the AR signaling process. By blocking the AR at multiple points, apalutamide and enzalutamide significantly reduce the growth-promoting effects of residual androgens. The common biological goal is to slow or stop the progression of prostate cancer.
Distinct Treatment Indications
Despite their shared mechanism, the two drugs have developed distinct clinical profiles based on the specific patient populations they were studied in and subsequently received regulatory approval for. Their indications are often framed around two concepts: “castration resistance” and “hormone sensitivity.” Prostate cancer is considered “castration-resistant” (CRPC) when it continues to progress even after castration has lowered testosterone levels. Conversely, “hormone-sensitive” (HSPC) cancer is still responsive to androgen deprivation therapy.
Apalutamide is approved for non-metastatic Castration-Resistant Prostate Cancer (nmCRPC), meaning the cancer is progressing despite low testosterone but has not yet spread to distant sites. It is also approved for metastatic Hormone-Sensitive Prostate Cancer (mHSPC), where the cancer has spread but is still responsive to hormone manipulation.
Enzalutamide has a broader range of approved indications, covering all three major stages of advanced prostate cancer. Like apalutamide, it is approved for nmCRPC and mHSPC. Uniquely, enzalutamide also holds an indication for metastatic Castration-Resistant Prostate Cancer (mCRPC). mCRPC is the most advanced stage of the disease, where the cancer has spread and is no longer controlled by standard hormone therapy.
Comparative Safety Profiles and Drug Interactions
The most significant differences between apalutamide and enzalutamide lie in their side-effect profiles and how they interact with other medications. These differences are often the deciding factors when a physician selects one treatment over the other. The risk of seizures is a known concern for both drugs, but enzalutamide has historically been associated with a higher incidence compared to apalutamide, though the risk is low for both.
Specific adverse events also vary between the two agents. Apalutamide is notably associated with a higher incidence of skin rash, which occurred in up to 27.8% of patients in some studies, often requiring dose adjustments or discontinuation. This dermatological reaction is thought to be related to the drug’s unique chemical structure. Apalutamide has also been linked to a higher risk of hypothyroidism and fracture.
Enzalutamide, on the other hand, is more commonly linked to central nervous system (CNS) side effects, including fatigue and mental impairment disorders. While both drugs can cause fatigue, the incidence can be higher with enzalutamide. Enzalutamide has also been associated with higher rates of hypertension and cardiovascular events. Both drugs carry a risk of falls and fractures.
A major pharmacological distinction between the two ARPIs is their potential for drug-drug interactions, which is determined by their effect on cytochrome P450 (CYP) enzymes in the liver. Both are potent inducers of several CYP enzymes, which can speed up the metabolism of other drugs taken concurrently, potentially reducing the effectiveness of those medications.
Specific Enzyme Induction Profiles
Enzalutamide is classified as a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Apalutamide is a strong inducer of CYP3A4, CYP2C19, and CYP2C9. These differences in enzyme induction mean that patients taking other medications—such as blood thinners, immunosuppressants, or certain heart medications—may require closer monitoring or dose adjustments. The specific profile of enzyme induction dictates which other medications must be avoided or closely managed, making this a determining factor for patients with multiple health conditions.