In an elderly male taking apalutamide (Nubeqa) and relugolix (Orgovyx), could his irritability be a side effect of the combined androgen deprivation therapy, and how should it be evaluated and managed?

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Irritability in an Elderly Male on Nubeqa and Orgovyx: Evaluation and Management

Irritability is a well-documented side effect of combined androgen deprivation therapy (ADT), and in this patient receiving both apalutamide (Nubeqa) and relugolix (Orgovyx), the symptom is most likely attributable to the profound testosterone suppression from this dual hormonal blockade.

Understanding the Mechanism

The combination of an androgen receptor pathway inhibitor (ARPI) like apalutamide with a GnRH antagonist like relugolix creates profound androgen deprivation. Research demonstrates that ADT causes significant mood changes including increased irritability, depression, tension, anxiety, and fatigue compared to baseline 1. These neuropsychological symptoms are common and often underestimated in clinical practice 2.

The mechanism involves:

  • Direct testosterone suppression from relugolix (maintaining castrate levels <50 ng/dL) 3
  • Additional androgen receptor blockade from apalutamide at the cellular level
  • Central nervous system effects from androgen withdrawal affecting mood regulation and cognitive function 1

Clinical Evaluation

Assess the following specific parameters:

  • Severity and timing: When did irritability begin relative to treatment initiation? Is it worsening or stable?
  • Associated mood symptoms: Screen for depression (PHQ-9), anxiety, fatigue, and cognitive changes
  • Testosterone levels: Confirm castrate levels are being maintained (should be <50 ng/dL) 3
  • Cardiovascular status: Relugolix has favorable cardiovascular safety compared to GnRH agonists 4, but assess for hypertension or other cardiovascular symptoms
  • Other medication side effects: Hot flashes, fatigue, anemia, and metabolic changes can compound mood symptoms 2
  • Baseline function: Compare to pre-treatment mood and cognitive status

Management Algorithm

Step 1: Confirm ADT-related etiology

  • Rule out disease progression, metabolic derangements (anemia, thyroid dysfunction), or unrelated psychiatric conditions
  • Review concomitant medications that may worsen mood (corticosteroids if on abiraterone, other CNS-active drugs)

Step 2: Non-pharmacologic interventions (initiate immediately)

  • Exercise programs improve mood, fatigue, and muscle mass in men on ADT 2
  • Cognitive behavioral therapy or supportive counseling for mood symptoms 5
  • Partner/family education about expected mood changes

Step 3: Pharmacologic management if symptoms persist or are severe

  • Selective serotonin reuptake inhibitors (SSRIs) for depression/irritability
  • Anxiolytics for anxiety if prominent
  • Consider referral to psychiatry for refractory symptoms

Step 4: Reassess treatment necessity

  • In the context of advanced prostate cancer requiring both agents, continuation is typically necessary for disease control 6
  • However, if the patient has non-metastatic castration-resistant prostate cancer (nmCRPC) and quality of life is severely impacted, discuss risks/benefits of continuing dual therapy versus ADT monotherapy
  • Do not discontinue therapy without oncology consultation, as this may compromise cancer control

Important Caveats

Common pitfall: Dismissing mood symptoms as "normal aging" or "expected" without adequate intervention. These symptoms significantly impact quality of life and treatment adherence 5, 2.

Safety consideration: The combination of relugolix with apalutamide has been studied and shows no new safety signals beyond the individual agents 7, 8. Most adverse events are grade 1-2, with irritability and mood changes being part of the expected ADT side effect profile 1, 2.

Reversibility: If treatment is eventually discontinued, testosterone recovery occurs more rapidly with relugolix (oral GnRH antagonist) compared to injectable GnRH agonists 4, which may lead to faster resolution of mood symptoms. However, in the context of advanced prostate cancer, indefinite ADT is typically required 9.

Documentation and Follow-up

  • Document baseline mood assessment and serial monitoring using validated tools (PHQ-9, GAD-7)
  • Schedule follow-up within 2-4 weeks after initiating mood interventions
  • Coordinate care with oncology to ensure cancer control is not compromised while addressing quality of life

References

2
Research

Management of side effects of androgen deprivation therapy.

Endocrinology and metabolism clinics of North America, 2011

5
Guideline

american cancer society prostate cancer survivorship care guidelines.

Ca-A Cancer Journal for Clinicians, 2014

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