Overview of Prostate Cancer Treatment
Prostate cancer treatment for metastatic castration-resistant disease (mCRPC) has expanded dramatically with novel androgen receptor pathway inhibitors (enzalutamide, apalutamide, darolutamide), PARP inhibitors for HRR gene-mutated disease (olaparib, rucaparib, talazoparib), and radiopharmaceuticals targeting PSMA (lutetium Lu-177 vipivotide tetraxetan). Treatment selection depends on castration status, prior therapies, genomic alterations, and disease burden.
Treatment Strategy by Disease Stage
Metastatic Castration-Sensitive (mCSPC)
- ADT backbone + intensification with AR inhibitors (apalutamide, enzalutamide, darolutamide+docetaxel) or abiraterone
- Triplet therapy for high-volume disease
Non-Metastatic CRPC (nmCRPC)
- Enzalutamide, apalutamide, or darolutamide to delay metastasis
Metastatic CRPC (mCRPC)
- AR inhibitors if not used in earlier line
- PARP inhibitors for BRCA/HRR mutations: olaparib, rucaparib, talazoparib+enzalutamide, niraparib+abiraterone
- Lutetium-177 PSMA (Pluvicto) for PSMA-positive mCRPC
- Radium-223 (Xofigo) for symptomatic bone metastases
- Docetaxel and cabazitaxel chemotherapy
Epidemiology & Impact
Prostate cancer is the most commonly diagnosed non-skin cancer in men in the United States, with an estimated 299,010 new cases and 35,250 deaths in 2024. Approximately 1 in 8 men will be diagnosed during their lifetime. The disease shows striking racial disparities: African American men have a 70% higher incidence rate and more than double the mortality rate compared to White men, reflecting a complex interplay of genetic susceptibility, tumor biology, and socioeconomic factors. The overall five-year survival rate is 97%, though this masks the poor prognosis of metastatic disease (5-year survival ~32%). Following the 2012 USPSTF recommendation against routine PSA screening, there was a concerning 5% increase in metastatic disease at diagnosis, prompting the 2018 guideline revision endorsing shared decision-making for men aged 55-69.
Molecular Biology & Biomarkers
The molecular landscape of prostate cancer has become increasingly relevant to treatment decisions. Approximately 20-25% of metastatic castration-resistant prostate cancers harbor defects in homologous recombination repair (HRR) genes, most commonly BRCA2 (~12%), BRCA1 (~1-2%), ATM (~6%), CDK12 (~5%), and CHEK2 (~3%). These alterations confer sensitivity to PARP inhibitors and are now routinely tested. Mismatch repair deficiency (dMMR/MSI-H), present in ~3-5% of advanced cases, predicts response to pembrolizumab. PSMA (prostate-specific membrane antigen) expression on tumor cells enables both diagnostic imaging (PSMA PET/CT, which has largely replaced conventional imaging for staging) and therapeutic targeting with lutetium-177 PSMA (Pluvicto). Emerging biomarkers include PTEN loss, TP53/RB1 co-deletion (associated with aggressive neuroendocrine transformation), and AR splice variants (AR-V7) that predict resistance to AR-targeted therapies.
Evolving Treatment Landscape
The prostate cancer treatment landscape has shifted toward treatment intensification at earlier disease stages. Landmark trials (LATITUDE, STAMPEDE, ENZAMET, TITAN, ARCHES, ARASENS) have established that adding novel hormonal agents or docetaxel to ADT in metastatic castration-sensitive prostate cancer (mCSPC) improves overall survival, making intensified first-line therapy the new standard. In the mCRPC space, the approval of PARP inhibitors — olaparib (alone and with abiraterone), rucaparib, talazoparib (with enzalutamide), and niraparib+abiraterone (Akeega) — has created a precision medicine paradigm based on HRR gene status. Lutetium-177 PSMA (Pluvicto), approved in 2022 for PSMA-positive mCRPC, established radioligand therapy as a new modality, with the PSMAfore trial demonstrating benefit in earlier treatment lines. The field is moving toward theranostic approaches where PSMA PET imaging directly guides treatment selection, and combination strategies pairing radioligand therapy with immunotherapy or PARP inhibitors are in active development.
Approved Therapies
Treatment Landscape
First-line mCRPC: Abiraterone, enzalutamide, or apalutamide with ADT. For HRR mutations (BRCA1/2), olaparib after progression. Later lines: Cabazitaxel chemotherapy or Pluvicto radioligand therapy for PSMA-positive disease.