Residency · Residency · Urology

Advanced and Metastatic Prostate Cancer

Overview

The biology of castration-resistant prostate cancer (CRPC) centers on persistent androgen receptor (AR) signaling despite androgen deprivation. This understanding has driven the development of multiple systemic therapies, including AR-targeted agents such as enzalutamide and abiraterone, chemotherapies like docetaxel and cabazitaxel, radioligand therapy with Lu-PSMA-617, and PARP inhibitors for DNA repair-deficient tumors. Treatment sequencing strategies are critical to optimize outcomes in this evolving therapeutic landscape.

Definitions and Disease States

Biochemical recurrence (BCR) after definitive treatment is defined differently depending on the initial therapy. After radical prostatectomy (RP), BCR is confirmed by a prostate-specific antigen (PSA) level of ≥0.2 ng/mL. Following radiation therapy, the Phoenix definition applies, where BCR is identified as a PSA rise of 2.0 ng/mL above the nadir. It is important to note that not all patients with BCR will progress clinically; the PSA doubling time (PSADT) is a key factor guiding management decisions.

Metastatic hormone-sensitive prostate cancer (mHSPC) includes patients presenting with de novo metastatic disease or those who develop metastatic recurrence after local therapy. This disease remains responsive to testosterone, and the treatment paradigm has shifted significantly, with androgen deprivation therapy (ADT) alone no longer considered sufficient.

Non-metastatic castration-resistant prostate cancer (nmCRPC) is characterized by rising PSA levels despite castrate testosterone levels (<50 ng/dL) but without detectable metastases on conventional imaging. A PSADT of 10 months or less identifies a high-risk subgroup warranting intervention.

Metastatic castration-resistant prostate cancer (mCRPC) is defined by disease progression—whether biochemical, radiographic, or clinical—despite castrate testosterone levels. The majority of mCRPC remains driven by AR signaling. Advances in therapy have extended median survival from approximately 18 months to over 30 months.

Androgen Receptor Biology in CRPC

Contrary to the term "castration-resistant," CRPC is not hormone-insensitive. AR signaling persists through various mechanisms. These include AR gene amplification and overexpression, which increase receptor levels; point mutations in the AR that broaden ligand specificity; and the expression of AR splice variants such as AR-V7, which is constitutively active and lacks the ligand-binding domain. Additionally, intratumoral androgen synthesis occurs via adrenal precursors and intracrine production, sustaining AR activation. Alterations in co-activator and co-repressor balances further modulate AR activity, and the glucocorticoid receptor pathway can bypass AR blockade. Understanding these mechanisms is essential for selecting appropriate AR-pathway-targeted therapies.

Treatment of mHSPC

The foundation of treatment for mHSPC is ADT, achieved through luteinizing hormone-releasing hormone (LHRH) agonists like leuprolide or goserelin, antagonists such as degarelix or relugolix, or bilateral orchiectomy. Orchiectomy offers immediate, permanent testosterone suppression and is cost-effective, though it may be psychologically challenging. The therapeutic goal is to reduce testosterone levels below 50 ng/dL, with some advocating for levels under 20 ng/dL.

ADT alone is no longer adequate for mHSPC; treatment intensification with combination therapy is now mandatory. The addition of docetaxel chemotherapy to ADT has demonstrated overall survival (OS) benefits, particularly in high-volume disease defined by visceral metastases or four or more bone metastases with at least one outside the axial skeleton, as shown in the CHAARTED trial. The STAMPEDE trial confirmed OS benefits across all disease volumes. Docetaxel is administered at 75 mg/m² every three weeks for six cycles.

Combining ADT with abiraterone plus prednisone also improves OS in high-risk and high-volume mHSPC, as evidenced by the LATITUDE and STAMPEDE trials, and benefits extend to low-volume disease. Abiraterone is given at 1000 mg daily with prednisone 5 mg daily.

ADT combined with enzalutamide has shown improved radiographic progression-free survival (rPFS) and OS in the ENZAMET and ARCHES trials. Enzalutamide is dosed at 160 mg daily and is generally well tolerated, with fatigue, hypertension, and rare seizure risk as notable side effects.

Similarly, apalutamide added to ADT improves rPFS and OS across all mHSPC patients, as demonstrated in the TITAN trial. Apalutamide is administered at 240 mg daily, with common adverse effects including skin rash (25%), hypothyroidism, and fatigue.

Triplet therapy combining ADT, darolutamide, and docetaxel has emerged from the ARASENS trial, showing significant OS benefit compared to ADT plus docetaxel alone. Darolutamide has low central nervous system penetration and fewer drug interactions, making triplet therapy increasingly favored for high-volume mHSPC. However, optimal patient selection between doublet and triplet regimens remains a subject of ongoing discussion.

Radiation therapy to the primary tumor improves OS in patients with low-volume mHSPC, as shown in the STAMPEDE arm H study, but does not confer benefit in high-volume disease. Radiation is now considered standard for low-volume de novo mHSPC.

Treatment of nmCRPC

For patients with high-risk nmCRPC, defined by a PSADT of 10 months or less, AR-targeted therapies are indicated to delay metastasis and maintain quality of life. Enzalutamide, apalutamide, and darolutamide have all demonstrated significant improvements in metastasis-free survival (MFS) in the PROSPER, SPARTAN, and ARAMIS trials, respectively. These agents also show overall survival benefits on updated analyses. Darolutamide is noted for its favorable safety profile.

Treatment of mCRPC

First-line treatment options for mCRPC depend on prior therapies and patient fitness. Abiraterone plus prednisone improves rPFS and OS in chemotherapy-naive patients, as shown in the COU-AA-302 trial, provided it was not previously used in the mHSPC setting. Enzalutamide similarly improves outcomes in chemo-naive mCRPC, with evidence from the PREVAIL trial. Docetaxel chemotherapy, administered at 75 mg/m² every three weeks for up to 10 cycles, was the first agent to demonstrate OS benefit in mCRPC (TAX 327 trial) but requires monitoring for neutropenia and neuropathy.

Second-line and subsequent therapies include cabazitaxel, which has shown OS benefit after docetaxel in the TROPIC trial and superiority over an alternative AR-targeted agent following prior AR therapy plus docetaxel in the CARD trial. Radium-223, an alpha emitter targeting bone metastases, improves OS in symptomatic bone-predominant mCRPC without visceral metastases (ALSYMPCA trial). Sipuleucel-T, an autologous dendritic cell vaccine, offers a modest OS benefit but has limited adoption. Lu-PSMA-617 and PARP inhibitors are emerging options discussed below.

Sequencing principles emphasize avoiding the sequential use of two AR-targeted agents due to cross-resistance limiting efficacy. After progression on AR-targeted therapy, switching to taxane chemotherapy is preferred. Biomarker-directed therapy, including PSMA-PET imaging and homologous recombination repair (HRR) mutation testing, increasingly guides treatment sequencing. The CARD trial supports cabazitaxel over a second AR agent after progression on prior AR therapy plus docetaxel.

PSMA-Targeted Theranostics

PSMA-PET imaging utilizes gallium-68 or fluorine-18 labeled PSMA ligands, offering superior sensitivity and specificity compared to conventional imaging modalities such as bone scans and CT. This imaging detects disease at lower PSA levels, including biochemical recurrence, and is essential for selecting patients for Lu-PSMA-617 therapy.

Lu-PSMA-617 (lutetium-177 vipivotide tetraxetan, Pluvicto) is a radioligand therapy that couples a beta-emitting radionuclide to a PSMA-targeting ligand. The VISION trial demonstrated improved rPFS (8.7 vs. 3.4 months) and OS (15.3 vs. 11.3 months) in mCRPC patients previously treated with an AR agent and taxane chemotherapy. The PSMAfore trial showed superiority of Lu-PSMA-617 over a change in AR-targeted therapy in taxane-naive mCRPC after progression on one AR agent. Treatment requires PSMA-PET-positive disease, defined by at least one PSMA-positive lesion without dominant PSMA-negative lesions. Side effects include fatigue, dry mouth, nausea, cytopenias (notably thrombocytopenia), and renal toxicity. The therapy is administered every six weeks for six cycles and is moving earlier in the treatment sequence based on emerging data.

PARP Inhibitors and DNA Repair Deficiency

Homologous recombination repair (HRR) gene alterations are present in a significant subset of mCRPC patients. BRCA2 mutations are the most common, occurring in about 10% of cases, with additional mutations in BRCA1, ATM, PALB2, CHEK2, CDK12, and others. Approximately 12% of mCRPC patients harbor germline mutations, with an additional 10-15% having somatic mutations. Current guidelines recommend germline and somatic HRR testing for all mCRPC patients.

Olaparib, a PARP inhibitor, improved rPFS and OS in the PROfound trial among patients with BRCA1/2 or ATM alterations after progression on AR agents and is FDA-approved for BRCA-mutated mCRPC. The PROpel trial showed that olaparib combined with abiraterone improved rPFS in first-line mCRPC regardless of HRR status, leading to FDA approval for BRCA-mutated disease in combination.

Rucaparib has demonstrated activity in BRCA-altered mCRPC in the TRITON2 and TRITON3 trials and is FDA-approved for BRCA1/2-mutated mCRPC after AR agent and taxane therapy.

The MAGNITUDE trial showed that niraparib combined with abiraterone improved rPFS in BRCA-mutated mCRPC, resulting in FDA approval for this combination.

Talazoparib combined with enzalutamide improved rPFS in HRR-deficient mCRPC in the TALAPRO-2 trial and is FDA-approved for HRR-mutated mCRPC.

Bone Health and Supportive Care

Bone-targeted agents are essential in managing mCRPC with bone metastases. Denosumab, a RANKL inhibitor, reduces skeletal-related events and is an effective option alongside zoledronic acid, a bisphosphonate alternative. Monitoring calcium levels and supplementing with calcium and vitamin D are necessary to prevent hypocalcemia. Dental evaluation prior to initiating these agents is important due to the risk of osteonecrosis of the jaw.

ADT contributes to bone loss, warranting DEXA scan monitoring, exercise, and supplementation with calcium and vitamin D. Anemia management typically involves transfusions as erythropoietin is rarely used. Pain from bone metastases can be addressed with palliative radiation. Spinal cord compression requires urgent MRI, administration of dexamethasone, and prompt radiation or surgical decompression.

<image>A treatment algorithm flowchart for advanced prostate cancer showing disease state progression from mHSPC through nmCRPC to mCRPC. Each state branches to recommended treatment options with key clinical trial names annotated. mHSPC shows ADT-based doublet and triplet combinations; nmCRPC shows AR-targeted agents; mCRPC shows first-line, second-line, and biomarker-directed options (PSMA-targeted therapy, PARP inhibitors). Arrows indicate sequencing principles and cross-resistance patterns. Color-coded by drug class: AR-targeted (blue), chemotherapy (green), radioligand (orange), PARP inhibitors (purple). Clinical algorithm format.</image>

<image>A diagram illustrating the mechanisms of castration resistance in prostate cancer. Central androgen receptor with multiple bypass and amplification pathways labeled: AR gene amplification, AR mutations, AR splice variants (AR-V7), intratumoral steroidogenesis, glucocorticoid receptor crosstalk, and neuroendocrine transdifferentiation. Each mechanism is paired with the therapeutic agent that targets it (e.g., abiraterone blocks CYP17 for intratumoral synthesis, enzalutamide blocks AR ligand binding). Molecular biology illustration style with cell membrane and nuclear compartments.</image>

<image>A visual summary of the PSMA theranostics paradigm showing the diagnostic-therapeutic cycle: PSMA-PET/CT scan (gallium-68 or fluorine-18 PSMA ligand) identifying PSMA-positive metastatic lesions, followed by Lu-PSMA-617 treatment targeting those same lesions with beta radiation. Includes a simplified diagram of the PSMA molecule on the prostate cancer cell surface, the radiolabeled ligand binding, and the therapeutic radiation effect. Key VISION trial outcomes annotated. Medical illustration with molecular and imaging components.</image>

Clinical Pearls

ADT alone is no longer an acceptable first-line therapy for metastatic hormone-sensitive prostate cancer; all patients should receive combination therapy, either doublet or triplet regimens. Triplet therapy with ADT, darolutamide, and docetaxel offers the greatest survival benefit in high-volume mHSPC but requires careful patient selection based on chemotherapy fitness. Detection of the AR-V7 splice variant via liquid biopsy can predict resistance to AR-targeted therapies and guide the choice toward taxane chemotherapy, although this approach is not yet universally adopted. Germline genetic testing for HRR mutations is recommended for all patients with metastatic prostate cancer, as it informs eligibility for PARP inhibitors and has implications for family cancer screening. Sequential use of two AR-targeted agents, such as abiraterone followed by enzalutamide, has limited efficacy due to cross-resistance; thus, switching drug classes after progression is advised. Lu-PSMA-617 therapy requires PSMA-PET-positive disease; patients with PSMA-negative or FDG-dominant disease are not candidates and may harbor more aggressive neuroendocrine biology. Radiation to the primary tumor improves overall survival in low-volume mHSPC and should be discussed with all newly diagnosed low-volume metastatic patients.

References

• Sweeney CJ, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer (CHAARTED). N Engl J Med. 2015;373(8):737-746
• Fizazi K, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer (LATITUDE). N Engl J Med. 2017;377(4):352-360
• Smith MR, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer (ARASENS). N Engl J Med. 2022;386(12):1132-1142
• Sartor O, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer (VISION). N Engl J Med. 2021;385(12):1091-1103
• de Bono J, et al. Olaparib for metastatic castration-resistant prostate cancer (PROfound). N Engl J Med. 2020;382(22):2091-2102
• NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 4.2024

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