Molecularly Guided Treatment Intensification in Metastatic Prostate Cancer

Andrew Hahn, MD, MD Anderson Cancer Center, Houston, Texas, presents a case of de novo metastatic prostate cancer to illustrate how comprehensive molecular profiling can inform upfront treatment selection.

He reviews the role of germline and somatic next-generation sequencing, transcriptomic profiling, and PTEN assessment in identifying opportunities for treatment intensification with PARP inhibitors, chemotherapy, or targeted therapy alongside ADT and androgen receptor pathway inhibition. Dr Hahn highlights emerging evidence for biomarker-driven approaches while emphasizing the importance of integrating molecular findings with disease characteristics, patient fitness, comorbidities, and treatment goals.

Transcript:

Hi, my name is Andy Hahn, I'm an assistant professor of GU medical oncology at MD Anderson Cancer Center with a focus on prostate cancer.

For today's case, we're going to review the management of de novo metastatic prostate adenocarcinoma. There's a full case synopsis that you can read with this video, but to highlight a few key points, this is a 74-year-old patient who presented with a very high PSA of 450 and underwent PSMA PET imaging that showed a primary prostate tumor, numerous bone metastases, and lung metastases.

We obtained a biopsy, which showed high-grade Gleason group adenocarcinoma. At the first visit, he was started on androgen deprivation therapy with degarelix to lower his testosterone, and we also performed molecular characterization.

When he returned to clinic about a month later, his PSA had fallen from 450 to 20. The molecular characterization was most notable for somatic DNA next-generation sequencing showing a pathogenic BRCA2 loss. PTEN was intact by immunohistochemistry, and those were probably the key highlights.

The clinical question is: what additional treatment would you recommend for this patient with metastatic hormone-sensitive prostate cancer, or what is now called androgen pathway modulator-sensitive, (APMS) prostate cancer?

The options are ADT plus an ARPI plus docetaxel as triplet therapy; ADT monotherapy; ADT plus an ARPI plus a more contemporary triplet with a PARP inhibitor; or a triplet with ADT, abiraterone, and capivasertib.

In my view, the correct answer is C, although I'm sure you can debate components of that, and I'll try to walk you through why I think that's the right answer for this case.

One of the key take-home points from this case is the importance of molecularly characterizing patients with de novo metastatic prostate cancer when you first see them in clinic, rather than waiting until their disease progresses.

For this patient, we first determined whether he was PSMA-avid by obtaining a PSMA PET scan. We then performed germline and somatic DNA next-generation sequencing. We also obtained a Decipher RNA expression score looking at 22 selected genes that can help inform the utility of chemotherapy. Finally, we evaluated PTEN loss by immunohistochemistry, which can inform the potential use of capivasertib.

I'm going to walk you through the evidence supporting each of those in a second. Before I do that, I also want to point out that our terminology is evolving. We used to call this metastatic hormone-sensitive prostate cancer. Per PCWG4, the new terminology is metastatic androgen pathway modulator-sensitive, or APMS, prostate cancer. It's exactly the same disease—we're simply moving toward terminology that is more patient friendly.

The big picture from a treatment perspective is that treatment is intensifying for metastatic APMS prostate cancer. In my view, option B is really the only clearly incorrect answer. There is no role for ADT monotherapy anymore. The minimum standard of care in 2026 is ADT plus an androgen receptor pathway inhibitor, or ARPI. The four available ARPIs are abiraterone, enzalutamide, apalutamide, and darolutamide. The molecular characterization that I already described helps inform whether adding a third agent is appropriate, together with the patient's goals, comorbidities, and performance status.

In this case, the patient had a somatic BRCA2 loss that we believed was driving the disease, and that led us to choose option C—ADT plus an ARPI plus a PARP inhibitor in the upfront APMS setting.

That recommendation is based on 2 clinical trials: the AMPLITUDE trial and TALAPRO-3. In both of these studies, a PARP inhibitor was added in the APMS setting, and the addition of a PARP inhibitor significantly improved radiographic progression-free survival compared with ADT plus an ARPI alone.

Currently, the only approval we have in this space comes from the AMPLITUDE trial, which added niraparib to abiraterone and ADT specifically for patients with BRCA2 alterations in the APMS setting. We're still waiting to see the exact package insert from TALAPRO-3 and whether the indication will be limited to BRCA2 or expanded to all homologous recombination repair alterations.

But these studies really move PARP inhibitors from the metastatic androgen pathway modulator-resistant setting into the APMS setting, and that informed the choice in this case.

Now, what if our patient didn't have a BRCA2 alteration? How do we choose between adding docetaxel or considering capivasertib?

We can look at the 2025 Cell paper from the UK STAMPEDE group by Dr Gerhardt Attard and Dr Emily Grist, which showed that the Decipher gene expression score can help identify who benefits most from upfront docetaxel. Patients with very high Decipher scores may be ideal candidates for upfront docetaxel, together with considerations such as de novo high-volume disease, age, and comorbidities.

Looking at option D, if this patient did not have a BRCA2 alteration, we would then evaluate the degree of PTEN loss to determine whether capivasertib should be added. Capivasertib in the upfront APMS setting was approved in June 2026 based on a registrational phase 3 trial showing a significant improvement in radiographic progression-free survival.

However, the approval is very specifically limited to patients with greater than or equal to 90% loss of PTEN protein by immunohistochemistry. Again, this highlights the importance of molecular characterization in selecting treatment appropriately. Many of the changes I've reviewed today came through in 2026.

Honestly, even in expert hands, we still don't know exactly what to do with overlapping biomarkers, and there are likely more approvals coming. The most important point is to molecularly characterize patients early and then engage in shared decision-making regarding the appropriate treatment intensity.

My final point is that many patients with advanced prostate cancer are older, frail, or have significant medical comorbidities. For some of those patients, ADT plus an ARPI alone is still the right answer, regardless of what the molecular characterization shows. It's perfectly reasonable to take that approach depending on patient goals and patient factors.

Thank you for joining me for this case today. I hope this was helpful, and please reach out if I can be of any help.