Introduction
History of Present Illness
Welcome. Your patient today is Kai W.
Kai W. is a 67-year-old man with a history of high-grade prostate adenocarcinoma (Gleason 4+4=8), diagnosed 4 years ago and initially managed with radical prostatectomy with pelvic lymph node dissection, which was negative for nodal involvement, followed by adjuvant radiation therapy for persistently detectable PSA, the radiation therapy was delivered to the prostate bed only; no pelvic nodal radiation was given. At the time of diagnosis his PSA was 27.8 ng/mL,serum testosterone was 312 ng/dL and computed tomography as well as bone scan were negative for metastatic disease. He experienced a biochemical recurrence 2 years after initial therapy; PSA was 6.3 ng/mL, and he was started on androgen deprivation therapy (ADT), with an initial response a year ago, with PSA suppression (3.3 ng/mL) and castrate testosterone levels (12.10 ng/dL), and remained on ADT.
During a routine visit 10 months ago, Kai’s PSA was found to be rising again (18.7 ng/mL), accompanied by new-onset bone pain. A bone scan and computed tomography (CT) imaging revealed widespread osseous metastatic disease involving both axial and appendicular skeleton, including long bones such as the femur and humerus, with ≥4 metastatic sites, including appendicular locations. Based on a somatic BRCA2 mutation identified through next-generation sequencing (NGS) of circulating tumor DNA, he was then managed with enzalutamide and talazoparib, which resulted in a PSA decline from 18.7 ng/mL to 4.5 ng/mL after 2 months. However, biochemical progression was observed after 5 months (7.8 ng/mL). He then received 6 cycles of docetaxel chemotherapy, leading to a transient stabilization of PSA levels at 1.2 ng/mL. However, PSA plateaued and subsequently began to rise again, reaching 4.4 ng/mL at his most recent assessment.
Over the past 2 weeks, Kai has developed increasing fatigue, new right hip pain, and peripheral neuropathy. He new neurologic symptoms or weight loss.
Family and Social History
He has no personal or family history of other BRCA-associated cancers, although he does report a paternal uncle with early-onset pancreatic cancer.
Physical Examination Notes
Physical examination reveals an alert, well-nourished man with stable vital signs, no focal neurologic deficits, mild tenderness over the lower spine, and new localized tenderness over the right hip, without signs of cord compression.
Review of Systems
Reports fatigue, intermittent lower back and right hip pain. weight loss, hematuria, or neurologic symptoms.
Consultation
Ask the patient — choose a question to play the interview.
Full transcript below
Transcript · Ask about his experience with the chemotherapy
Doctor: Hi Kai, good to see you again. How have you been feeling since starting the chemotherapy?( 7 seconds pause, actor is listening and looking to the camera)
Kai: Hey, Doc. I’ve been hanging in there, but the last few weeks have been rougher. The fatigue started to wear me down. Some days I feel like I don’t have the energy for anything.
Doctor: I’m sorry to hear that. Is the fatigue pretty constant, or does it vary throughout the day?( 7 seconds pause, actor is listening and looking to the camera)
Kai: It’s pretty constant now. Not debilitating, but worse than when I started the treatment.
Doctor: Okay. What about pain—any changes there?( 6 seconds pause, actor is nodding and looking to the camera)
Kai: Yeah. I’ve been getting this nagging pain in my right hip. It’s not sharp, but it’s deep and achy. Sitting too long worsens it, and it’s started bothering me at night.
Doctor: That sounds uncomfortable. Any changes in how you move around or walk? ( 7 seconds pause, actor is listening and looking to the camera)
Kai: Not limping or anything, just slower, I guess—trying not to aggravate it.
Doctor: Got it. Any new numbness, weakness, or bladder/bowel issues? ( 7 seconds pause, actor is nodding and looking to the camera)
Kai: I’ve experienced pain, tingling sensations in my hands, and fatigue.
Doctor: That helps. What about your appetite? Any nausea or changes there? (7 seconds pause, actor is listening and looking to the camera)
Kai: No, nothing like that.
Doctor: Thanks for sharing that. I’m also seeing that your PSA has started to rise again, to 4.4 since your last labs, which, along with your symptoms, could suggest the treatment might be losing effectiveness. No weight loss? ( 18 seconds pause, actor is nodding and looking to the camera)
Kai: Maybe a pound or 2, but I’m not sure. Nothing major.
Doctor: Okay. It’s helpful to get the full picture. We’ll do some updated imaging and labs to check for progression. But whatever we find, we’ll work through it together—strong treatment options are still ahead.( 12 seconds pause, actor is nodding and looking to the camera)
Tests
Select appropriate tests for the patient — order and sequence are part of the exercise.
Conventional imaging
Laboratory panel
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/CT
Diagnoses
Select the best diagnosis.
Your first answer is recorded before any feedback is shown — commit to the diagnosis you would act on.
Would you like to change your diagnosis?
Your first answer stays on the record either way; a revision is recorded separately.
Existing Diagnoses
| Name | Start date | End date |
|---|---|---|
| Localized prostate cancer | … | … |
| Metastatic castration-resistant prostate cancer (mCRPC) | … | Ongoing |
Decisions
Medication selection · non-medication orders.
Existing Prescriptions
Leuprolide
Dose: 22.5 mg · Route: subcutaneous · Frequency: every 3 months
Radical prostatectomy with pelvic lymph node dissection
Surgery
Adjuvant radiation therapy
Dose: 66 Gy
Enzalutamide
Dose: 160 mg · Route: oral · Frequency: once daily
Talazoparib
Dose: 1 mgRoute: oral · Frequency: once daily
Docetaxel
Dose: 75 mg/m² IV · Frequency: every 3 weeks
Medication Selection
Choose the medication you would prescribe for this patient. Your first selection is recorded before any feedback is shown.
Non-Medication Orders
Choose the additional clinical interventions you would order to manage the patient effectively.
Laboratory panel
PSA
Case Review
This case followed the clinical course of a patient with BRCA2-mutated mCRPC, highlighting a treatment pathway that prioritizes molecularly targeted therapy. Following biochemical progression after enzalutamide and talazoparib and 6 cycles of docetaxel chemotherapy, the patient was initiated on the PARP inhibitor talazoparib. While he initially demonstrated PSA stabilization, his subsequent biochemical and symptomatic progression prompted evaluation for PSMA-directed RLT.
Through genomic profiling and advanced imaging, the patient was confirmed to have PSMA-positive disease and no visceral involvement. Although multiple therapeutic options exist at this point in care, the case explored why re-treatment with PARP inhibition is inappropriate after progression, and why PSMA-directed RLT became an option once the disease has progressed despite targeted therapy.
This case also reviewed real-world aspects of managing PARP inhibitor therapy, including the need for toxicity monitoring, recognition of treatment failure, and strategies for transitioning to subsequent lines of treatment. The case author's decision to integrate ¹⁷⁷Lu-PSMA-617 into the patient’s treatment plan reflects a biomarker-driven, evidence-based approach aligned with current treatment guidelines .
Clinical Pearls
- The ESMO and EAU guidelines recommend PARP inhibitors such as rucaparib and talazoparib for use in patients with mCRPC harboring BRCA mutations .
- Hematologic monitoring is essential during PARP inhibitor therapy, as it is associated with cytopenias that may require dose modifications or treatment discontinuation .
- ESMO and EAU guidelines recommend ¹⁷⁷Lu-PSMA-617 for patients with PSMA-positive mCRPC following prior treatment with ARPI .
- PSMA PET imaging is crucial for determining eligibility for RLT and is more sensitive than conventional imaging for detecting disease progression in mCRPC .
- Although PSA is commonly used for monitoring, PSMA PET/CT may offer added value in detecting progression in selected cases, particularly when PSA kinetics are inconclusive. However, its routine use remains debated due to cost, accessibility, and a lack of definitive survival benefit .
- Ordering a PSMA PET scan to monitor treatment response and disease progression is appropriate only when prompted by clinical or biochemical evidence of progression. PSMA PET-CT has been found to outperform traditional imaging methods in detecting recurrent disease . PSMA PET is not recommended for routine surveillance in asymptomatic patients with stable PSA.
- PSMA PET/CT for treatment response evaluation is superior to PSA response for predicting survival, and it detects disease progression earlier than PSA levels in patients with mCRPC. This can affect treatment decisions and improve patient outcomes .
- Although PSMA PET provides important information about treatment response, its results must be interpreted cautiously. Scans performed too soon after therapy may not accurately reflect disease activity, and ARPI can influence PSMA expression, potentially causing false-positive results. Reduced tracer uptake or tumor shrinkage may be misleading, as these findings could reflect tumor dedifferentiation rather than true response, leading to underestimation of disease progression .
Targeted, mechanism-based therapy in patients with mCRPC
PARP inhibitors should be prioritized for patients with mCRPC who harbor BRCA1/2 mutations. The PROfound trial showed that Olaparib significantly prolonged overall survival compared to switching to a second ARPI in men with BRCA alterations who had progressed on prior ARPI therapy . This supports the use of PARP inhibition as a targeted, mechanism-based therapy for patients with BRCA1/2 alterations following prior ARPI exposure. In Kai’s case, talazoparib was selected as recommended by ESMO and EAU clinical practice guidelines .
Considerations for switching
Switching therapies in mCRPC requires careful consideration of disease progression patterns, prior treatment response, molecular profile, and treatment-related toxicity. A rising PSA alone may not always mandate a change. Still, when accompanied by radiographic progression or clinical symptoms, a transition to the next line of therapy should be considered . Importantly, international guidelines discourage switching between agents with similar mechanisms of action, such as from one ARPI to another .
Biomarker-driven options offer greater therapeutic value, such as switching to ¹⁷⁷Lu-PSMA-617 in PSMA-positive patients . Toxicity management, patient fitness, and goals of care should also inform the timing and type of switch .
Considerations for Sequencing
Optimal sequencing of therapies in mCRPC is critical to maximizing clinical benefit and preserving quality of life . As the treatment landscape expands with targeted therapies such as PARP inhibitors and RLT, selecting the right agent at the right time, based on prior treatment exposures, molecular characteristics, and disease burden, can significantly influence outcomes . Guidelines emphasize that the choice and order of systemic therapies should be individualized , as improper sequencing may lead to diminished efficacy, overlapping toxicities, or missed opportunities for life-prolonging treatment. Strategic sequencing allows clinicians to build durable treatment plans that adapt to evolving resistance mechanisms and leverage each therapy’s strengths .
According to the updated ESMO and EAU clinical practice guidelines, patients with mCRPC and BRCA1/2 alterations should be offered talazoparib following progression on a novel ARPI, with or without prior taxane chemotherapy. For patients who have progressed after both ARPI and taxane treatment, ¹⁷⁷Lu-PSMA-617 is recommended for those with PSMA-positive disease. These recommendations reflect a structured, biomarker-driven approach to sequencing systemic therapies in advanced prostate cancer . RLT should be integrated into the management of patients with PSMA-positive mCRPC. Its use is guided by PSMA expression on imaging .
Clinical Evidence Supporting RLT
The evidence for integrating RLT into advanced prostate cancer care rests on several pivotal trials, which have demonstrated the efficacy and safety of PSMA-targeted agents such as¹⁷⁷Lu-PSMA-617.
The VISION trial established the clinical utility of RLT in the post-androgen receptor signaling inhibitor (ARSi) and post-taxane space. In the VISION trial, ¹⁷⁷Lu-PSMA-617 was administered on top of standard of care, which included continued ADT and allowed the addition of ARPIs (such as enzalutamide or abiraterone) and bone-protective agents per protocol. Therefore, it is appropriate to consider ARPI continuation or addition as part of the therapeutic combination when prescribing ¹⁷⁷Lu-PSMA-617 in alignment with the VISION protocol . In this phase 3 study, patients with PSMA-positive mCRPC who had progressed on both ARSis and taxane-based chemotherapy experienced significant improvements in both radiographic progression-free survival (8.7 vs 3.4 months; HR 0.40; p < 0.001) and overall survival (15.3 vs 11.3 months; HR 0.62; p < 0.001) compared to standard care alone .
Complementing this, the TheraP trial, a randomized phase 2 study, compared ¹⁷⁷Lu-PSMA-617 directly with cabazitaxel in men with mCRPC after docetaxel failure. The results showed superior PSA response rates (66% vs 37%), improved progression-free survival (HR 0.63; p = 0.0028), and a lower incidence of grade 3–4 adverse events (33% vs 53%) .
More recently, the PSMAfore trial explored ¹⁷⁷Lu-PSMA-617 before chemotherapy in patients who had failed one ARSi but had not yet received taxanes. The preliminary results of PSMAfore showed the potential of ¹⁷⁷Lu-PSMA-617 in improving patient outcomes in taxane-naïve patients with progressive mCRPC .
Considerations for integrating RLT into the Continuum of Care
The question of when to introduce RLT into the treatment sequence for mCRPC is rapidly evolving, shaped by both trial evidence and clinical pragmatism. Traditionally, RLT has been employed post-chemotherapy, as evidenced by the inclusion criteria of the VISION trial, which enrolled patients who had progressed after taxanes and at least one ARSi .
This positioning reflects a more refractory disease state, where RLT has demonstrated a clear survival benefit. However, treatment at this stage is often complicated by cumulative toxicities and reduced marrow reserve, making tolerability a concern. In contrast, pre-chemotherapy use of RLT is gaining support based on emerging evidence from the PSMAfore trial, which targeted a less heavily pretreated population . The preliminary results of PSMAfore are show the potential of ¹⁷⁷Lu-PSMA-617 in improving patient outcomes in taxane-naïve patients with progressive mCRPC. These findings suggest that earlier integration may yield better responses with potentially fewer adverse effects and could offer an alternative to chemotherapy in select patients.
PSMA PET imaging plays a critical role in selecting appropriate candidates for RLT. Guidelines recommend a PSMA PET-positive scan as a precondition for use . Thus, imaging acts not only as a biomarker of eligibility but also as a potential predictor of response. Altogether, these considerations support a more nuanced, patient-tailored approach to sequencing RLT, moving beyond a rigid post-chemotherapy placement toward more individualized integration based on biology, disease burden, and treatment history. This has particular relevance for chemo-ineligible or frail populations, including older patients or those with comorbidities, for whom chemotherapy may be contraindicated. RLT offers a targeted mechanism with less systemic toxicity, making it an attractive option in these patients .
- American Board of Internal Medicine (ABIM). Laboratory test reference ranges – January 2025. ABIM. 2025. Available from: https://www.abim.org/Media/bfijryql/laboratory-reference-ranges.pdf
- American College of Physicians. Reference ranges and laboratory values. ACP Internal Medicine Meeting. n.d. [cited 2025 July]. Available from: https://annualmeeting.acponline.org/educational-program/reference-ranges
- Antunac K, Beketić-Orešković L. How to optimally sequence available therapy lines in advanced prostate cancer. Acta Clin Croat. 2022;61(Suppl 3):32–44.
- Combes AD, Palma CA, Calopedos R, et al. PSMA PET-CT in the diagnosis and staging of prostate cancer. Diagnostics (Basel). 2022;12(11):2594.
- Cornford P, Tilki D, van den Bergh RCN, et al. EAU–EANM–ESTRO–ESUR–ISUP–SIOG guidelines on prostate cancer. 2025.
- Dawson NA, Leger P. Overview of the treatment of castration-resistant prostate cancer (CRPC) [UpToDate]. Waltham, MA: UpToDate, Inc.; 2025 [updated Mar 2025; cited 2025 Apr 3]. Available from: https://www.uptodate.com/contents/overview-of-the-treatment-of-castration-resistant-prostate-cancer-crpc
- Dean L. Blood groups and red cell antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2005. Table 1, Complete blood count. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2263/table/ch1.T1
- de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. New England Journal of Medicine. 2019;381(26):2506–2518.
- Emmett L, van der Walt R, Iravani A, et al. ENZAP: A randomized phase II study of enzalutamide prior to lutetium-177 PSMA-617 radioligand therapy in men with metastatic castration-resistant prostate cancer. J Nucl Med. 2023;64(3):421–428.
- Fizazi K, Gillessen S; ESMO Guidelines Committee. Updated treatment recommendations for prostate cancer from the ESMO Clinical Practice Guideline considering treatment intensification and use of novel systemic agents. Ann Oncol. 2023;34(6):557–63.
- Huang S, Ong S, McKenzie D, et al. Comparison of 18F-based PSMA radiotracers with [68Ga]Ga-PSMA-11 in PET/CT imaging of prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2024;27(4):654–64.
- Karpinski MJ, Rahbar K, Bögemann M, et al. Updated Prostate Cancer Risk Groups by Prostate-specific Membrane Antigen Positron Emission Tomography Prostate Cancer Molecular Imaging Standardized Evaluation (PPP2): Results from an International Multicentre Registry Study. Eur Urol. 2025. Available from: https://www.sciencedirect.com/science/article/pii/S0302283825002490.
- Konopnicki A, Zaliznyak M, Roy M, et al. The therapeutic use of 177Lu-PSMA-617 radioligand therapy in prostate cancer treatment: a review of literature and ongoing trials. Discov Oncol. 2024;15(1):791.
- Maiorano BA, De Giorgi U, Verzoni E, et al. Hematological toxicity of PARP inhibitors in metastatic prostate cancer patients with mutations of BRCA or HRR genes: a systematic review and safety meta-analysis. Target Oncol. 2024;19(1):1–11.
- Pluvicto. Summary of Product Characteristics. Novartis Europharm Limited; 2022. Available from: https://www.ema.europa.eu/en/documents/product-information/pluvicto-epar-product-information_en.pdf
- Rosar F, Neher R, Burgard C, Linxweiler J, Schreckenberger M, Hoffmann MA, et al. Upregulation of PSMA expression by enzalutamide in patients with advanced mCRPC. Cancers (Basel). 2022;14(7):1696.
- Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091–103.
- Seifert R, Emmett L, Rowe SP, et al. Second version of the Prostate Cancer Molecular Imaging Standardized Evaluation Framework including response evaluation for clinical trials (PROMISE V2). Eur Urol. 2023;83(5):405–12.
- Sengupta S, Krishnan MA, Chattopadhyay S, Chelvam V. Comparison of prostate-specific membrane antigen ligands in clinical translation research for diagnosis of prostate cancer. Cancer Rep (Hoboken). 2019 Aug;2(4):e1169.
- Tsai AK, Kagalwalla S, Langer J, et al. Pembrolizumab for metastatic castration-resistant prostate cancer: trials and tribulations. Expert Opin Biol Ther. 2024;24(1–2):51–62.
- U.S. Food and Drug Administration. Pluvicto (lutetium Lu 177 vipivotide tetraxetan) injection, for intravenous use. Prescribing information. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215833s000lbl.pdf
- Virgo KS, Rumble RB, Talcott J. Initial management of noncastrate advanced, recurrent, or metastatic prostate cancer: ASCO guideline update. J Clin Oncol. 2023;41(20):3652–6.
- Zhao S, Yu EY. Castrate-resistant prostate cancer: postdocetaxel management. Curr Opin Urol. 2013;23(3):201–7.
- Quinn DI, Sandler HM, Horvath LG, Goldkorn A, Eastham JA. The evolution of chemotherapy for the treatment of prostate cancer. Ann Oncol. 2017;28(11):2658-69.
Metastatic castration-resistant prostate cancer — Case II · Or.01.25 · Kai W.
Faculty — Boris Hadaschik MD PhD, Elena Castro MD PhD, Laurence Klotz, CM, MD, FRCSC, Stefano Fanti MD and Wolfgang Fendler MD
Supporter — Novartis