Would androgen deprivation therapy with leuprolide or goserelin, and possibly bicalutamide, be the next step for an elderly male with a history of prostate cancer, increased PSA to 7, PIRADS 5 on MRI, and no metastasis on PSMA PET scan?

Androgen Deprivation Therapy for Biochemically Recurrent Prostate Cancer After Radiation

Yes, androgen deprivation therapy with leuprolide or goserelin should be initiated for this patient with biochemically recurrent, locally advanced nonmetastatic prostate cancer after radiation therapy. 1

Primary Recommendation: ADT Plus Abiraterone and Prednisolone

ADT plus abiraterone and prednisolone should be considered as the preferred treatment rather than castration monotherapy alone, based on strong evidence from the STAMPEDE trial showing significant failure-free survival benefit. 1 This combination demonstrated a 79% relative improvement in failure-free survival (time to biochemical failure, disease progression, or death) for patients with nonmetastatic disease who had undergone radiation therapy. 1

Key Evidence Supporting Combination Therapy

• The STAMPEDE trial mandated radiation therapy to the primary for patients with newly diagnosed node-negative, nonmetastatic disease, making this evidence directly applicable to your patient. 1
• Treatment duration with abiraterone was 2 years or less in the trial, providing a defined treatment endpoint. 1
• This represents high-quality evidence (evidence quality: high; strength of recommendation: strong) from the 2021 ASCO guideline. 1

Alternative Option: Combined Androgen Blockade

If abiraterone is not available or affordable, combined androgen blockade using ADT (leuprolide or goserelin) plus bicalutamide may be offered as an alternative to castration monotherapy. 1 This recommendation is based on:

• Recent meta-analyses showing improved progression-free survival with combined androgen blockade versus castration alone. 1
• Japanese registry data (8,826 patients) demonstrating median time to progression of 11.6 years with combined androgen blockade versus 7.1 years with castration monotherapy (HR 0.78, P < .001). 1
• Evidence quality is high, though strength of recommendation is moderate. 1

Specific Regimen for Combined Androgen Blockade

• Leuprolide or goserelin for medical castration. 1
• Bicalutamide 50 mg daily (80 mg was used in Japanese studies but 50 mg is the FDA-approved dose for combination therapy). 1, 2
• Monitor liver function tests at baseline, regularly for the first 4 months, then periodically, as hepatotoxicity occurs in approximately 1% of patients. 2

Timing: Early (Immediate) ADT is Preferred

Early initiation of ADT is recommended over deferred therapy for this patient with biochemically recurrent disease after radiation. 1 The rationale includes:

• Meta-analyses show modest but statistically significant benefit in overall survival and cancer-specific survival with early ADT in locally advanced nonmetastatic disease. 1
• Evidence quality is intermediate with moderate strength of recommendation. 1
• The PSA rise to 7 with PIRADS 5 lesion indicates high-risk biochemical recurrence requiring treatment. 1

Important Caveat About Deferred ADT

The 2021 ASCO guideline explicitly states: "No recommendation can be provided at this time for men with PSA relapse after local treatment. Although existing studies suggest a potential OS benefit, additional research is needed as such studies were underpowered." 1 However, given the PIRADS 5 lesion and PSA of 7, this represents high-risk recurrence where treatment is warranted rather than observation.

Consideration of Intermittent vs. Continuous ADT

Intermittent ADT may be offered as an alternative to continuous therapy to reduce side effects while maintaining disease control. 1 Key points:

• Meta-analyses demonstrate noninferiority of intermittent ADT compared to continuous ADT with respect to overall survival in biochemically recurrent disease. 1
• This approach allows treatment breaks to mitigate ADT side effects including cardiovascular risk, metabolic changes, and bone loss. 3, 4
• Close monitoring of PSA and testosterone levels during off-treatment periods is required. 5

When Continuous ADT is Mandatory

Continuous ADT must be maintained if the patient develops metastatic disease or castration-resistant prostate cancer, as testosterone suppression remains essential for any subsequent therapy to work effectively. 5

Critical Monitoring and Side Effect Management

Baseline and Ongoing Assessments

• Liver function tests before starting bicalutamide, then regularly for 4 months, then periodically. 2
• Glucose monitoring, as ADT reduces glucose tolerance and may manifest as diabetes. 2
• Bone density assessment and consideration of bisphosphonates or denosumab for osteoporosis prevention. 5, 3
• Cardiovascular risk assessment, as ADT increases cardiovascular morbidity. 3, 4
• PSA monitoring every 3-6 months to assess treatment response. 2

Expected Side Effects to Counsel Patient About

• Hot flashes occur in 53% of patients on combination therapy. 2
• Gynecomastia and breast pain occur in up to 38-39% with bicalutamide monotherapy. 2
• Metabolic effects including lipid alterations, insulin resistance, obesity, and sarcopenia. 3, 4
• Increased cardiovascular events and osteoporosis risk. 3, 4

Common Pitfalls to Avoid

Do not use ADT monotherapy without considering combination therapy, as this represents suboptimal treatment based on current evidence. 1 The STAMPEDE trial clearly demonstrated superior outcomes with ADT plus abiraterone versus ADT alone in this exact clinical scenario.

Do not defer treatment in this patient with PIRADS 5 lesion and PSA of 7, as this represents high-risk biochemical recurrence requiring intervention. 1 Deferred ADT should be restricted to asymptomatic patients with lower-risk features.

Do not forget to monitor for antiandrogen withdrawal phenomenon if the patient later progresses on bicalutamide. 2 Some patients experience PSA decline and clinical improvement when bicalutamide is discontinued while continuing the LHRH analog.

If the patient is on warfarin or other coumarin anticoagulants, closely monitor PT/INR when starting bicalutamide, as excessive prolongation has been reported with serious bleeding complications. 2

Algorithm for Treatment Selection

1. First-line preferred: ADT (leuprolide or goserelin) + abiraterone + prednisolone for 2 years. 1

2. If abiraterone unavailable/unaffordable: ADT (leuprolide or goserelin) + bicalutamide 50 mg daily. 1

3. If patient desires to minimize side effects: Consider intermittent ADT schedule with close PSA/testosterone monitoring. 1

4. If patient has significant cardiovascular disease: Discuss risks/benefits carefully, as ADT increases cardiovascular morbidity; consider cardiology consultation. 3, 4

5. Continue ADT indefinitely unless patient develops intolerable side effects, very limited life expectancy from other causes, or explicitly chooses comfort-focused care. 5