Teaching pack: Prostate cancer

Prostate cancer is the most common cancer in men in most high-income countries and the second leading cause of male cancer death. It is a spectrum: most PSA-detected disease is indolent and safely watched (ProtecT: ~3% prostate-cancer mortality at 15 years whatever the strategy), while de novo metastatic disease remains lethal within a median of about five years despite modern therapy. Diagnosis now runs PSA → multiparametric MRI (PRECISION) → targeted biopsy → Grade Group, with germline and somatic HRR testing for advanced disease and PSMA PET for staging (proPSMA) and recurrence. Digital-pathology AI (ArteraAI Prostate, 2025) and gene-expression classifiers (Decipher) refine who needs treatment and who benefits from adding hormone therapy.

Treatment is built on androgen deprivation, the first targeted cancer therapy (Huggins, 1941). Metastatic hormone-sensitive disease is treated with doublets (ADT + abiraterone, enzalutamide, apalutamide or darolutamide) or triplets adding docetaxel (ARASENS, PEACE-1), and since 31 July 2026 with 177Lu-PSMA-617 added to ADT + ARPI (PSMAddition, rPFS HR 0.72). PTEN-deficient disease gained capivasertib + abiraterone in 2026. In castration-resistant disease the sequence includes ARPI switch, PARP inhibitors for HRR-mutant tumours (PROfound, PROpel, TALAPRO-2 with OS benefit), docetaxel and cabazitaxel, radium-223 for bone-only disease, and 177Lu-PSMA-617 before or after chemotherapy (VISION, PSMAfore). Enzalutamide is approved even for high-risk PSA-only recurrence (EMBARK).

• Theranostic pairing of PSMA PET and Pluvicto.
• Genotype-directed doublets.
• AI pathology guiding ADT duration.
• Radioligand therapy across the metastatic continuum: 177Lu-PSMA-617 approved post-taxane (2022), pre-taxane (2025), and at first metastatic diagnosis with ARPI (31 July 2026).
• Triplet therapy (ADT + ARPI + docetaxel) for high-volume de novo disease, with OS HR ~0.7 (ARASENS, PEACE-1).
• Genotype-directed doublets: PARP inhibitor + ARPI for HRR-mutant (OS benefit in TALAPRO-2) and capivasertib + abiraterone for PTEN-deficient disease (2026).

1. 1941Huggins: castration controls prostate cancer
2. 1941Huggins shows castration controls metastatic prostate cancer
3. 1966Gleason grading system published
4. 1986PSA test approved for monitoring; screening spreads in the 1990s
5. 2004Docetaxel: first chemotherapy to extend survival (TAX 327)
6. 2011Abiraterone approved
7. 2011Abiraterone approved; enzalutamide follows in 2012
8. 2013Radium-223: first alpha emitter approved
9. 2013Radium-223: first alpha emitter approved (ALSYMPCA)
10. 2015CHAARTED and STAMPEDE: docetaxel at first metastatic diagnosis

• Actinium-225 PSMA agents (product)
• Ifinatamab deruxtecan (product)
• Capivasertib (product)
• Tarlatamab (product)
• AlphaBreak (FPI-2265) & AcTION (225Ac-PSMA-617) (trial)
• Xaluritamig (product)
• XALute (trial)
• Pasritamig (product)
• Mevrometostat (product)
• MEVPRO-1 (trial)
• 177Lu-PSMA-I&T (product)
• ECLIPSE (trial)

• ARASENS (phase 3, n=1,306): Overall survival: 48.9 months, HR 0.68
• LATITUDE (phase 3, n=1,199): Overall survival: 53.3 months vs 36.5 months, HR 0.66
• PEACE-1 (phase 3, n=1,173): Overall survival, abiraterone vs no abiraterone (with ADT + docetaxel): 66 months vs 52 months, HR 0.75
• VISION (phase 3, n=831): Overall survival: 15.3 months vs 11.3 months, HR 0.62
• CHAARTED (E3805) (phase 3, n=790): Overall survival: 57.6 months vs 44 months, HR 0.61
• ARCHES (phase 3, n=1,150): Radiographic progression-free survival: 19 months, HR 0.39

• Overdiagnosis vs. underdiagnosis in screening.
• Neuroendocrine transformation.
• Ac-225 supply.
• Screening trade-off: PSA reduces mortality by ~20% but overdiagnoses; MRI-first and risk-adapted intervals are only partly adopted.
• Neuroendocrine / lineage-plastic transformation in ~15-20% of late mCRPC has no targeted therapy; DLL3 and B7-H3 agents are being borrowed from SCLC.
• AR-V7 and N-terminal-domain resistance: masofaniten failed; AR degraders remain preclinical/early.

1. What is brachytherapy and where is it essential?
   Answer

   Placing a radioactive source directly inside or next to the tumour; essential in cervical cancer, used in prostate (seeds or HDR), breast, skin, and eye melanoma.
2. Who should have germline genetic testing when diagnosed with cancer?
   Answer

   All patients with TNBC, ovarian, pancreatic, or metastatic prostate cancer, increasingly all breast cancer, and anyone with suggestive family history; results change surgery, drug choice (PARP inhibitors), and family screening.
3. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
4. What questions should someone newly diagnosed with triple-negative breast cancer ask before surgery?
   Answer

   Whether chemo-immunotherapy before surgery (KEYNOTE-522) is planned and why; germline BRCA testing; PD-L1 and HER2-low status; TIL score; clinical trial options; fertility preservation; breast-conserving versus mastectomy and sentinel node approach; what response (pCR/RCB) will mean for treatment afterwards.
5. What is the first T-cell engager to improve survival in a common solid tumour?
   Answer

   Tarlatamab (Imdelltra), DLL3×CD3, in second-line small-cell lung cancer: OS 13.6 vs 8.3 months in DeLLphi-304.
6. What is theranostics and what is the best-known example?
   Answer

   Using the same targeting molecule for a diagnostic scan and a treatment: PSMA PET shows where prostate cancer is, and 177Lu-PSMA-617 (Pluvicto) delivers radiation to the same target.

• Wikipedia: https://en.wikipedia.org/wiki/Prostate_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459