Case · Presentation

Four years, three systemic therapies, and the PSA is climbing again.

Kai W. is 67. High‑grade prostate adenocarcinoma, Gleason 4+4=8, diagnosed four years ago at a PSA of 27.8 ng/mL with negative CT and bone scan. Radical prostatectomy with pelvic node dissection, node negative, then adjuvant radiation to the prostate bed for a persistently detectable PSA.

Biochemical recurrence two years later at 6.3 ng/mL took him on to androgen deprivation. Ten months ago the PSA turned again at 18.7 with new bone pain, and imaging showed widespread osseous disease across the axial and appendicular skeleton. A somatic BRCA2 mutation on circulating‑tumour‑DNA sequencing led to enzalutamide and talazoparib, then six cycles of docetaxel.

Past two weeks

Fatigue, right hip pain, peripheral neuropathy

Gleason

4+4=8 · somatic BRCA2

Order the workup or use the arrow keys

Case · Workup

PSA 22.3. And the PET says the disease is PSMA‑avid.

Today's panel: PSA 22.3 ng/mL, testosterone 11.62 ng/dL — castrate. Alkaline phosphatase 203 U/L, LDH 211 U/L, haemoglobin 9.2 g/dL, haematocrit 34%, white cells 3.6 × 10⁹/L, RBC 3.9 × 10¹²/L — anaemia, leukopenia and a low red‑cell count.

⁶⁸Ga‑PSMA‑11 PET/CT shows extensive PSMA‑avid disease through the axial and appendicular skeleton, SUV_max 6.4 to 14.2. By PROMISE V2 this is miM1b (diss) with no miN1, mM1a or miM1c involvement; expression score 3, PSMA‑TV 20 mL. By PPP2, high risk.

Conventional imaging agrees and adds nothing: bone scan positive at widespread skeletal sites, chest CT clear, abdominopelvic CT showing no visceral or nodal disease.

PROMISE V2

miM1b (diss)

PPP2 risk group

High

Visceral disease

None

Nodal disease

None

Go to the decision

Case · Decision

Fourteen options. Which would you start?

He has had an ARPI, a PARP inhibitor and a taxane. Choose one.

• AApalutamide
• BDarolutamide
• CCabazitaxel
• DDocetaxel
• EEnzalutamide
• F¹⁷⁷Lu‑PSMA‑617
• G¹⁷⁷Lu‑PSMA‑617 + ARPI
• HNiraparib + abiraterone
• IOlaparib + ARPI
• JRadium‑223
• KPembrolizumab
• LRucaparib
• MSipuleucel‑T
• NTalazoparib + enzalutamide

Each option is offered alongside a bone‑protective agent.

Lock in my answer Select a regimen to continue

Case · Verdict

Four are appropriate. Ten are not.

• F¹⁷⁷Lu‑PSMA‑617AppropriateGuideline‑concordant after an ARPI and taxane chemotherapy in PSMA‑positive disease. VISION (Sartor O, et al. 2021; Konopnicki A, et al. 2024).
• G¹⁷⁷Lu‑PSMA‑617 + ARPIAppropriateAuthorized in the EU with ADT, with or without an ARPI, after an ARPI and a taxane (Lutetium Lu 177 vipivotide tetraxetan, SMPC. 2025).
• CCabazitaxelAppropriateCARD: superior rPFS and overall survival against switching to a second hormonal agent after docetaxel and an ARPI (de Wit R, et al. 2019).
• JRadium‑223AppropriateFor symptomatic bone‑predominant disease with no visceral metastases (Fizazi K, Gillessen S. 2023).
• H I L NPARP inhibitors — niraparib, olaparib, rucaparib, talazoparibNot appropriateHe has already progressed on talazoparib, indicating resistance to the class. In the next line, agents with a different mechanism should be used to overcome acquired resistance (Antunac K, Beketić‑Orešković L. 2022; Cornford P, et al. 2025).
• A BApalutamide, darolutamideNot appropriateRecommended within ESMO and EAU guidelines for mHSPC and nmCRPC. Not used in the mCRPC setting (Fizazi K, Gillessen S. 2023; Cornford P, et al. 2025).
• EEnzalutamideNot appropriateAlready received with talazoparib, with only a short‑lived PSA response. CARD found switching to a second ARPI inferior to a mechanistically distinct agent (de Wit R, et al. 2019).
• DDocetaxelNot appropriateBenefit is best established in chemotherapy‑naïve patients, and he has progressed while on this agent (Quinn DI, et al. 2017).
• KPembrolizumabNot appropriateUsed where tumours are MSI‑H or dMMR. His tumour is microsatellite stable with intact mismatch repair genes (Tsai AK, et al. 2024).
• MSipuleucel‑TNot appropriateAvailable in the US only, indicated for asymptomatic or minimally symptomatic patients and generally reserved for the chemotherapy‑naïve setting (Zhao S, Yu EY. 2013).

See what settles it

Case · Evidence

Progression on a class is a reason to leave it.

Genomic profiling and PSMA PET confirmed PSMA‑positive disease with no visceral involvement. The case explores why re‑treatment with PARP inhibition is inappropriate after progression, and why PSMA‑directed radioligand therapy becomes an option once the disease has progressed despite targeted therapy.

• 01Change the mechanism. In the next treatment line, agents with different mechanisms of action should be used to overcome acquired resistance (Antunac K, Beketić‑Orešković L. 2022).
• 02PSMA PET decides eligibility. Metastases must show PSMA expression above liver parenchyma — score 2 or higher on PROMISE V2 — and the PET is more sensitive than conventional imaging for progression (Combes AD, et al. 2022).
• 03Watch the marrow. Hematologic monitoring is essential during PARP inhibitor therapy, which is associated with cytopenias that may require dose modification or discontinuation (Maiorano BA, et al. 2024).
• 04Scan on cause, not on schedule. PSMA PET is appropriate only when prompted by clinical or biochemical evidence of progression, and is not recommended for routine surveillance in asymptomatic patients with stable PSA.

Start the case