Resuming Xtandi After Leg Pain with Negative Imaging
It is safe to resume Xtandi (enzalutamide) in this patient, as leg pain is not a recognized adverse effect of enzalutamide, and the unremarkable MRI and ultrasound effectively rule out serious pathology such as deep vein thrombosis or skeletal-related events. 1
Evidence-Based Safety Profile of Enzalutamide
The FDA prescribing information for Xtandi does not list leg pain or lower extremity pain as a recognized adverse effect 1. The most common clinically relevant adverse events associated with enzalutamide include:
- Fatigue (most common dose-limiting toxicity) 2, 1
- Hot flushes 2
- Diarrhea 2
- Arthralgias (joint pain, not specifically leg pain) 3
- Hypertension 2
- Seizures (0.6% in clinical trials) 2, 1
Clinical Reasoning for Safe Resumption
The temporal association between starting Xtandi and developing leg pain does not establish causation when the symptom is not part of the drug's known adverse effect profile. 1 The negative imaging studies are particularly reassuring because they exclude:
- Deep vein thrombosis (which would be visible on ultrasound)
- Skeletal-related events such as pathologic fracture or bone metastases causing pain (which would be visible on MRI) 2
- Soft tissue pathology requiring intervention
Recommended Management Algorithm
Resume Xtandi at full dose (160 mg daily) with close monitoring for symptom recurrence. 1 The FDA dosing guidelines specify that dose modifications are warranted only for Grade 3 or higher adverse reactions or intolerable adverse reactions 1. Since leg pain is not a recognized enzalutamide adverse effect and imaging is negative, this does not meet criteria for dose reduction.
Monitoring Strategy:
- Assess leg pain severity at 1-2 weeks after resumption to determine if symptoms recur with rechallenge 1
- If pain recurs and worsens, consider alternative etiologies including:
- Musculoskeletal causes (lumbar radiculopathy, peripheral vascular disease)
- Progression of bone metastases (repeat imaging if clinically indicated) 2
- Concurrent medication effects from Orgovyx (relugolix)
Important Caveat:
If the patient develops Grade 3 or intolerable symptoms upon rechallenge, withhold Xtandi for one week until symptoms improve to Grade 2 or less, then resume at reduced dose (120 mg or 80 mg). 1 However, this scenario is unlikely given that leg pain is not an established enzalutamide adverse effect.
Survival Benefit Justifies Continuation
Enzalutamide provides substantial mortality benefit that should not be abandoned without clear evidence of drug-related toxicity. In the PREVAIL trial, enzalutamide reduced the risk of death by 29% (HR 0.71,95% CI 0.60-0.84, P<0.001) in chemotherapy-naïve metastatic castration-resistant prostate cancer 4. The ARCHES trial demonstrated 61% reduction in risk of radiographic progression or death (HR 0.39,95% CI 0.30-0.50, P<0.001) 2. Discontinuing effective therapy based on an unrelated symptom would compromise this survival advantage.
Alternative Explanation for Leg Pain
The leg pain more likely represents:
- Coincidental musculoskeletal pain unrelated to enzalutamide
- Deconditioning or sarcopenia from androgen deprivation therapy (both Orgovyx and Xtandi contribute to loss of muscle mass) 2
- Peripheral vascular disease in this age group (early 60s)
The fact that imaging is unremarkable and leg pain is not in the known adverse effect profile strongly supports that this is not drug-related toxicity requiring permanent discontinuation. 1