What are the recommended treatment options for metastatic prostate cancer?

Treatment of Advanced Metastatic Prostate Cancer

Immediate continuous androgen deprivation therapy (ADT) is the cornerstone first-line treatment for metastatic prostate cancer, and for patients fit enough to receive chemotherapy, combination therapy with ADT plus docetaxel significantly improves survival and should be strongly considered as the preferred initial approach. 1, 2

Initial Treatment for Metastatic Hormone-Naïve Prostate Cancer

Standard ADT Approaches

• Bilateral orchiectomy or LHRH agonists are the recommended methods for achieving castration 1
• When initiating LHRH agonist therapy, an antiandrogen must be administered for 3-4 weeks to prevent testosterone flare, which can temporarily worsen disease 1
• LHRH antagonists represent an alternative that avoids testosterone flare and can be used as initial treatment 1

Combination Therapy Considerations

• For patients with good performance status and metastatic hormone-naïve disease, ADT combined with docetaxel 75 mg/m² every 3 weeks provides superior overall survival compared to ADT alone 1, 2, 3
• Combined androgen blockade (adding antiandrogen to castration) provides no clinically relevant survival advantage over castration alone and is not recommended as routine practice 1
• Intermittent ADT is not recommended for metastatic disease outside clinical trials unless there is significant intolerance to continuous therapy, as it failed to demonstrate non-inferiority in survival 1

What NOT to Do Initially

• Concomitant bone-targeting therapy with denosumab or bisphosphonates is NOT recommended at initial diagnosis of metastatic hormone-naïve disease 1
• Concomitant cytotoxic chemotherapy beyond docetaxel is not recommended outside clinical trials 1
• Antiandrogen monotherapy shows inferior survival compared to castration and should not be used 1

Treatment of Castration-Resistant Prostate Cancer (CRPC)

First-Line Options for Metastatic CRPC

• Docetaxel 75 mg/m² every 3 weeks with prednisone remains the standard chemotherapy, demonstrating overall survival benefit in phase III trials 1, 3
• Docetaxel can be deferred in truly asymptomatic patients, but should be strongly considered in those with rapidly rising PSA, visceral metastases, or anaplastic features 1
• Continue ADT throughout CRPC treatment to maintain castrate testosterone levels 1

Post-Docetaxel Treatment Options

• For patients with good performance status who progress after docetaxel, the following agents have Level I evidence for survival benefit: cabazitaxel, abiraterone, enzalutamide, and radium-223 1
• Abiraterone and enzalutamide can also be used as first-line agents in asymptomatic or minimally symptomatic chemotherapy-naïve CRPC patients 2
• Radium-223 is specifically indicated for symptomatic bone-predominant metastases without visceral disease 2

Bone-Directed Therapy in CRPC

• In patients with bone metastases from CRPC at high risk for skeletal-related events, denosumab or zoledronic acid should be initiated, with denosumab showing superior delay in skeletal-related events 1, 2
• Zoledronic acid every 3-4 weeks is category 1 evidence for preventing pathologic fractures, spinal cord compression, and need for bone surgery or radiation 1
• Single-fraction external beam radiotherapy provides effective palliation for painful bone metastases 2

Monitoring and Surveillance

Essential Monitoring Parameters

• Clinical assessment and PSA measurement should be performed regularly 1, 2
• Initial staging with bone scan and CT/MRI of abdomen and pelvis is strongly recommended 1, 2
• Systematic imaging surveillance is NOT mandatory in absence of PSA rise or cancer-related symptoms 1, 2
• Monitor for ADT side effects including osteoporosis (bone densitometry) and metabolic syndrome 2

Critical Caveats

• PSA is unreliable in patients with undifferentiated or anaplastic metastatic prostate cancer with neuroendocrine features 1, 2
• Patients with Gleason 9-10 or those not responding to ADT should undergo biopsy of accessible lesions to identify neuroendocrine differentiation 1
• MRI of spine is recommended for patients with vertebral metastases to detect subclinical cord compression 2

Special Considerations and Pitfalls

Hepatotoxicity and Contraindications

• Avoid docetaxel in patients with bilirubin >ULN or AST/ALT >1.5× ULN with alkaline phosphatase >2.5× ULN, as these patients have increased risk of severe toxicity and treatment-related mortality 3
• Do not administer docetaxel to patients with neutrophil counts <1500 cells/mm³ 3
• Measure liver function tests prior to each docetaxel cycle 3

Neuroendocrine Differentiation

• Patients with neuroendocrine features should receive platinum-based chemotherapy (cisplatin/etoposide or carboplatin/etoposide) in addition to ADT 1, 2
• These patients often present with visceral metastases and may have disproportionately low PSA relative to disease burden 1

After Completing Novel Therapies

• For patients completing Pluvicto (177Lu-PSMA-617) with responding disease and high-volume residual tumor, extended therapy with additional cycles may be beneficial 4
• Those with progressive disease should transition to alternative systemic therapies including rechallenge with androgen receptor pathway inhibitors, taxane chemotherapy, or clinical trial enrollment 4