Androgen Modulation in Prostate Cancer Management

Androgens and their receptor play a central role in prostate physiology and tumourigenesis. Androgen deprivation therapy (ADT) remains the cornerstone of treatment for advanced and metastatic disease, yet most individuals eventually progress to castration-resistant prostate cancer (CRPC) through mechanisms including intratumoral androgen production, androgen receptor (AR) amplification, splice variant expression and adaptive signalling crosstalk. Second-generation AR inhibitors and androgen synthesis blockers have extended survival, but resistance invariably emerges. Combination strategies pairing AR blockade with DNA damage response inhibitors, immune-modulatory agents or novel antiandrogens aim to forestall or reverse resistance. Precision medicine approaches now integrate genomic stratification, biomarker-guided selection and liquid biopsy to tailor androgen-targeted treatments. Globally, these advances have transformed management paradigms from monotherapy to multi-agent regimens, underscoring the importance of tumour-host interactions, molecular heterogeneity and timing of intervention. Future directions focus on overcoming adaptive resistance, refining patient selection and developing agents that target AR cofactor complexes and non-canonical androgen pathways.

Research from Nature Portfolio

Recent clinical studies have explored strategies to overcome resistance in metastatic CRPC. One investigation demonstrated that blockade of CXCR2-mediated myeloid chemotaxis in combination with AR inhibition can reduce tumour-infiltrating myeloid cells, reverse resistance to AR signalling inhibitors and yield durable biochemical and radiological responses. Separately, a phase 3 trial evaluated the addition of a PARP inhibitor to enzalutamide in patients with HRR-deficient metastatic CRPC and showed a marked improvement in radiographic progression-free survival compared with AR blockade alone. These findings illustrate the potential of combinatorial approaches that integrate AR targeting with modulation of the tumour microenvironment and DNA repair pathways.

Androgen Modulation in Prostate Cancer Management publication trend

The graph below shows the total number of articles in androgen modulation in prostate cancer management across all publications each year (not limited to Nature Index journals).

Technical terms

Androgen receptor (AR): Nuclear receptor that mediates androgen-driven transcriptional programmes in prostate cells.

Androgen deprivation therapy (ADT): Treatment designed to reduce systemic androgen levels or block AR signalling.

Castration-resistant prostate cancer (CRPC): Prostate cancer that progresses despite castrate concentrations of serum testosterone.

Poly(ADP-ribose) polymerase (PARP) inhibitor: Drug that impedes a key DNA repair enzyme to exploit homologous recombination deficiencies.

CXCR2: Chemokine receptor involved in the recruitment of myeloid cells to the tumour microenvironment.

References

1. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene (2013).
2. Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance. Nature (2023).
3. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nature Medicine (2023).
4. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. Journal of Clinical Oncology (2019).
5. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Molecules (2022).