Podcast Summary: The Uromigos, Episode 464

#UromigosLive 2025 – The Evolving Landscape of mHSPC

Date: November 10, 2025
Hosts: Brian Rini, Tom Powles
Panelists: Chuck Ryan, Neeraj Agarwal, Michael Morris, Chris Sweeney, Tanya Dorff
Main Theme: Exploring advances and debates in the management of metastatic hormone-sensitive prostate cancer (mHSPC), particularly around adding a third agent to the ADT+ARPI backbone, interpreting biomarker-driven results, and prospects for treatment de-escalation.

Episode Overview

This episode convenes top genitourinary oncologists to discuss the rapidly shifting treatment paradigm for mHSPC. After introductions, panelists each present their perspective on a potential "third agent" (Lutetium, PARP inhibition, Docetaxel, AKT inhibition) that might be added to standard androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI), with Chuck Ryan presenting an argument for restraint and de-escalation. The session is interactive, with debates, cases, and data-driven discussions centering on the implementation of new trial evidence and patient subgroups.

Key Discussions & Insights

1. Triplets and Treatment Intensification

[02:59 – 10:42] – Tanya Dorff kicks off with Docetaxel

• Docetaxel use early in mHSPC had profound survival benefits in the CHARTED trial.
• ARPIs have also shown robust benefit; meta-analyses reveal high-volume disease/synchronous mets benefit from triplet regimens, while low-volume may need only doublets.
• Tanya highlights emerging evidence (ESMO, Decipher) on molecular signatures (e.g., PTEN) guiding treatment selection—patients with PTEN deletion may see unique benefit from docetaxel, whereas Decipher can help identify need for triplet therapy.
• Quote: “Wouldn’t we rather use molecular features, biology, and not only the clinical features?” – Tanya Dorff [04:04]

[05:31 – 10:42] – Panel’s Response: Biomarkers and Real-World Implementation

• Chuck Ryan is skeptical about large, prospective biomarker trials: “Are we going to really do another MHS PC study where we're going to use Decipher…as much as we'd love to do it I just don't think it's going to [happen].” [06:05]
• Michael Morris distinguishes between prognostic and treatment-selection biomarkers: PTEN loss may be more actionable if it's "druggable."
• Neeraj Agarwal warns that real-world practice lags, with about 30% of patients not receiving even ADT+ARPI.
• The consensus: Biomarker-driven treatment is promising but not ready for prime time—clinical features remain paramount.
• Memorable exchange:
  • “These are our tax dollars at work…” – Chuck Ryan [08:33]
  • Banter about physician intuition, trial design, and the importance of large cooperative group datasets.

2. PARP Inhibition in mHSPC

[10:59 – 15:46] – Neeraj Agarwal presents AMPLITUDE (Abiraterone + Niraparib)

• AMPLITUDE trial targeted mHSPC patients with specific homologous recombination repair (HRR) mutations.

• Primary endpoint: Radiographic progression-free survival (rPFS), met with a 52.5% relative risk reduction for BRCA1/2 mutated patients.

• These patients have particularly poor prognosis (control arm median PFS ~26 months).

• Secondary endpoints (overall survival) still immature; anemia (manageable with dose reductions) and hypertension are notable side effects.

• Quote: “Abiraterone plus niraparib should be considered as a standard of care for patients with MHSPC with BRCA1 and BRCA2 mutations.” – Neeraj Agarwal [13:30]

• Panel’s Take:

  • Michael Morris: Most would now treat BRCA-mutant mHSPC patients with this triplet (“Who among us would not give that?” [15:03])
  • Chris Sweeney presses about the exclusion of non-BRCA HRR patients in analyses, and low real-world docetaxel uptake.

• Chuck Ryan floats the idea of de-escalation: Could some BRCA patients drop abiraterone?

  • “Does this suggest that maybe the abiraterone, etc. is something that we could consider pulling out?” [19:21]

3. Radioligand Therapy: Lutetium in mHSPC

[20:23 – 24:03] – Michael Morris recaps PSMA Addition

• First randomized study of Lutetium-PSMA in mHSPC, on top of ADT+physician's choice of ARPI.
• RPFS benefit (HR: 0.72); OS data immature; increased toxicity, especially xerostomia.
• Discussion:
  • Chuck Ryan: Wonders about late toxicities from Lutetium, given potentially long remissions.
  • Neeraj: Celebrates the trial, notes differences in populations among recent studies, and reiterates docetaxel remains viable.
  • Michael Morris: Ongoing trials (ASPIRE, SWOG S2107) will clarify role of docetaxel intensification.
• Quote: “The issue that keeps coming up…was is the use of docetaxel which is the implicit control arm that has never been tested in these triplets.” – Michael Morris [24:10]

4. AKT Inhibition: Cautious Optimism

[25:13 – 29:59] – Chris Sweeney discusses AKT Inhibitors (Capivasertib, Ipatasertib)

• Trials show RPFS benefit for abiraterone+AKT in biomarker-selected mHSPC, especially with complete PTEN-loss, but OS inconsistent; toxicity (notably significant hyperglycemia) is a challenge.
• “AKT inhibition, it’s a great idea. It’s a biologic therapy. We have a target. The problem is we don’t know the right target.” – Chris Sweeney [25:20]
• Panel remains optimistic about future but notes need for better biomarker-driven patient selection and safety signals.
• Tanya Dorff: The same biomarker might predict benefit from other agents (“…it may not only apply to this drug.” [28:29])
• Chuck Ryan: “This is the beginning of a clinically validated conversation.” [27:53]

5. Do No Harm: Case-based De-Escalation

[30:26 – 36:49] – Chuck Ryan argues for finite therapy and selective intensification

• Presents a young patient with metachronous, oligometastatic prostate cancer; received doublet (ADT+Darolutamide) and stereotactic body radiotherapy (SBRT) with excellent PSA response.
• Chuck advocates for aggressive therapy followed by de-escalation, rather than indefinite triple intensification:
  • “First do a little bit of harm and then, back off ... Can we be having more and more of these conversations about even curing metastatic prostate cancer or at least driving a situation to having a long-term treatment free interval?” [33:54]
• Tanya Dorff: Reminds that NCCN doublet recommendations are based on conventional, not PET imaging; cautions against over-radiating PSMA PET findings.
• Panel generally supports finite duration of ADT+ARPI+SBRT in such cases (often 18–24 months).

Case Panel: Real-World Application

[38:47 – 49:53]
A series of cases are presented; panelists write down and justify treatment plans. Key scenarios:

• Case 1: 68-year-old, metachronous high-volume, ATM mutation (ECOG 1).

  • Most favor ADT + ARPI (doublet), discuss but are not enthusiastic about docetaxel (triplet) due to time course and favorable biology.
  • “This could suggest a slower biology...” – Chuck Ryan [39:33]

• Case 2: 68-year-old, oligometastatic recurrence, PSMA+ only, CHECK2 mutation.

  • Universal support for ADT + ARPI + SBRT for finite duration (1–2 years).

• Case 3: 58-year-old, de novo, high-volume, visceral mets, P53, RB, PTEN deleted.

  • Panel supports maximal intensification (triplet and then some): ADT + ARPI + docetaxel, possibly platinum in select “neuroendocrine” cases.
  • “I’m doing a quadruplet here … he’s going to be a neuroendocrine patient in about nine months.” – Chuck Ryan [46:41]

• Case 4: 68-year-old, BRCA2 mutation, PTEN deleted, equivocal liver, bone/lymph node mets.

  • Panel agrees BRCA2 trumps: ADT + ARPI + PARP inhibition is priority, possibly sequencing with chemo given logistics/toxicity.

Notable Quotes & Memorable Moments

| Time (MM:SS) | Speaker | Quote/Highlight | |---|---|---| | 04:04 | Tanya Dorff | "Wouldn’t we rather use molecular features, biology, and not only the clinical features?" | | 06:05 | Chuck Ryan | “Are we going to really do another MHS PC study where we're going to use Decipher…as much as we'd love to do it I just don't think it's going to [happen].” | | 08:33 | Chuck Ryan | “These are our tax dollars at work, by the way. Honestly, seriously…” | | 13:30 | Neeraj Agarwal | “Abiraterone plus niraparib should be considered as a standard of care for patients with MHSPC with BRCA1 and BRCA2 mutations…” | | 15:03 | Michael Morris | “Most people seeing this data had a patient walk in with a BRCA mutation …who among us would not give that.” | | 27:53 | Chuck Ryan | “This is the beginning of a clinically validated conversation.” | | 33:54 | Chuck Ryan | “First do a little bit of harm and then, back off on your harm or back off on your therapy.” |

Timestamps for Key Segments

• 02:59 – 10:42: Docetaxel/triplet therapy and role of biomarkers
• 10:59 – 15:46: AMPLITUDE trial and use of PARP inhibitors in HRR-mutated mHSPC
• 20:23 – 24:03: Radioligand (Lutetium-PSMA) therapy results and implications
• 25:13 – 29:59: AKT inhibition; biomarker/treatment matching
• 30:26 – 36:49: Case-based discussion on treatment de-intensification
• 38:47 – 49:53: Case panel: Real-world scenarios and panel’s treatment selections

Tone & Highlights

• The tone is frank, collegial, and occasionally playful ("Dr. Doolittle," “Dr. Do not Do Little”); the panel doesn’t shy from debate or questioning assumptions.
• Multiple reminders that the “real world” is not clinical trials—uptake of therapies like chemo (docetaxel) is modest outside trial settings.
• “Cooperative group” clinical trials (publicly funded) are celebrated for enabling robust, practice-changing science.

Conclusion

This episode serves as a state-of-the-field discussion on mHSPC: urging appropriate use of powerful new agents in the right hands, calling for pragmatic, thoughtful application of biomarkers, and anticipating a future where treatment is more tailored, yet mindful of duration and toxicity. The group’s nuanced, occasionally divergent takes reflect the complexity of the evolving therapeutic landscape—and the importance of both evidence and expert judgment.

Summary by topic:

• Triplet/Doublet Strategy: Clinical features and, increasingly, molecular biology help guide intensity.
• PARP Inhibitors: Transformative in BRCA+ mHSPC; less clear for non-BRCA HRR mutations.
• Lutetium: Effective, but long-term toxicity and role among multiple options requires more data.
• AKT Inhibition: Cautiously optimistic, with biomarker and safety caveats.
• De-Escalation: Finite, patient-tailored regimens for select patients; real-world vigilance essential.

Final Words: The mHSPC armamentarium is expanding rapidly—expert judgment remains paramount, and the goal should always be finding the “right therapy, for the right patient, for the right duration.”