Rewriting the Playbook: How Biomarker-Driven Therapy Is Transforming Metastatic Prostate Cancer Care

Prostate cancer treatment has entered one of its most active periods in years, with 4 vital new regimens gaining FDA approval in the metastatic hormone-sensitive prostate cancer (HSPC) setting alone within the past 12 months. That pace reflects a broader shift in the field: treatment selection is increasingly guided by tumor and germline genetics, with therapies targeting BRCA mutations and PTEN deficiencies as well as radioligand therapies being incorporated into existing androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI) combinations, rather than a one-size-fits-all approach to hormone-sensitive and hormone-resistant disease.

For Prostate Cancer Awareness Month, Manojkumar Bupathi, MD, MS, a medical oncologist at Rocky Mountain Cancer Centers who also leads genitourinary (GU) cancer trials at Sarah Cannon Research Institute in Denver, Colorado, spoke with Targeted Oncology^TM about how this biomarker-driven era is reshaping treatment decisions, what upfront germline and somatic testing now demands of community oncologists, and which emerging modalities including T-cell engagers, antibody-drug conjugates, and other newer drug classes could be practice-changing in the near future.

Targeted Oncology: How has the field of metastatic prostate cancer treatment changed compared with 5 years ago, particularly in the metastatic setting?

Manojkumar Bupathi, MD, MS: The landscape of prostate cancer has changed quite dramatically over the last 5 years, and even more so in the last 2 to 3 years. The number of options that patients have now for upfront [HSPC], as well as hormone-resistant prostate cancer, has—I wouldn't say exploded—but we definitely have a lot more therapies. We're pulling more effective therapies earlier, and we are also becoming more biomarker driven, meaning more patients are getting therapy that is more tailored to the genetics of their cancer, as well as to the genetics of the individual.

If [a patient] was born with a BRCA mutation now they can get a BRCA-directed therapy. This is based on the AMPLITUDE trial [NCT04497844]….¹ If they had more of a tumor-specific alteration, such as a PTEN deficiency, then they could get PTEN-directed therapy with an ARPI, so something like abiraterone [Zytiga], and that's based on a study called CAPItello-281 [NCT04493853].² We still have our previously approved therapies, such as chemotherapy, as well as the various ARPIs, such as darolutamide [Nubeqa], enzalutamide [Xtandi], abiraterone, as well as apalutamide [Erleada], and you also have your conventional ADT. We're probably going to be moving into an era where most patients are going to get more of a triplet therapy as opposed to a single agent or doublet therapy, and it's going to be tailored on the genetics of the individual as well as the clinical characteristics of what we're seeing from a cancer standpoint.

Could you describe the recent trials that have led to FDA approvals to treat patients with metastatic prostate cancer?

There were several trials that got [new regimens] approved. If we date back a year, one of them is ARANOTE [NCT02799602], which is using darolutamide and ADT without the use of docetaxel, and so darolutamide became another doublet that was being utilized in [HSPC].³ Further along the line would be the BRCA-mutated HSPC, and that is looking at a trial called AMPLITUDE.¹ This is the first major PARP inhibition that moved into HSPC, and that's using niraparib/abiraterone [Akeega] plus prednisone and ADT. Earlier this year, we saw PTEN-directed therapy, using capivasertib [Truqap], abiraterone, and prednisone, and so now PTEN is now being looked at as a frontline therapy, and evaluating for PTEN is also indicated in these patients.²

The most recent therapy that got approved in prostate cancer was a radioligand using lutetium Lu 177 vipivotide tetraxetan [Pluvicto], and this is based on the study called PSMAddition [NCT04720157], and this is moving radioligand therapy into HSPC.⁴ This was the most recent approval that we saw in prostate cancer as of July 2026.

So, we had 4 different approvals all in the same space of HSPC within the past year. We're basically seeing one every 2 to 3 months, which is exciting because it gives patients more options. This is on top of what has already been approved over the past few years.

How are these newer targetable biomarkers are helping to individualize the selection of treatment for these patients?

We have to look [at] genetic testing with BRCA. We have to look for the PTEN loss. We have to look to see if patients have RB1 and p53 [mutations]. We also have to look at the extent or volume of disease, and we also have to look at the characteristics, meaning the Gleason score. Do they have liver involvement, or is it only bone involvement, or is it a combination of liver, lung, or bone? Then, we have to look at the patient characteristics, meaning other comorbidities, blood [count] numbers, and then make a decision as to what would be the most effective therapy for these individuals.

If they have a PTEN loss, [we decide if] we are going to give them [capivasertib]. If they have a BRCA mutation, chances are they're going to get a PARP inhibitor. But if they have extensive disease and they don't have any of these alterations, then is [lutetium-177] the right option, or is it more chemotherapy? That is going to be dependent on the treating physician discussion and is going to highlight the importance of having a multidisciplinary team between urology, medical oncology, and radiation [oncology] to figure out what that next therapy is going to look like. For patients who don't have any actionable alteration, chances are they're going to get chemotherapy, ADT, and an ARPI as their treatment of choice.

Is the increase in these biomarker-driven therapies a challenging adjustment for oncologists treating prostate cancer?

It may be a slight adjustment because historically all these genetic markers were done at the time of hormone resistance. Now, we're saying that testing needs to happen upfront and should include both germline and somatic [testing]. You have to consider both to clearly understand the genetics before making a treatment decision.

What ongoing and future trials have the potential to be practice changing in prostate cancer?

There are a lot of exciting trials that are happening in prostate cancers. In a broad category, we have some exciting drug development that's happening with T cell engagers in prostate cancer, and T cell engagers have been shown to be at least in the hormone-resistant space, quite effective. A lot of these [therapies] are also moving up earlier and earlier. There is a number of these compounds that are available that have been shown to be effective, and now moving into larger-phase studies. Antibody-drug conjugates are another area that's still developing in prostate cancer, and that is moving forward as well.

One of the most exciting therapies that we're looking at in prostate cancer is a molecule called RIPTAC [regulated induced proximity targeting chimera], and that has driven a lot of excitement among investigators from physicians as well as even from patients because the toxicity seems to be quite minimal, but the effectiveness is quite high, and it's an oral pill. That's moving very rapidly as well. Hopefully, we'll see some of these molecules in the clinic available for all patients over the course of the next year, which will be tremendous.

What advice that you would give for oncologists in the community who are seeing these changes in clinical trials and considering changes to their treatment strategies?

I would say, don't be hesitant to reach out for guidance to your local [prostate specialist with whom] you feel comfortable in order to get some guidance. We give a lot of guidance on our podcast, Oncology Decoded, on GU cancers as well. Dr Garmezy and I talk about this all the time. There are a lot of resources that are available online as well as through educational avenues that can provide this. SCRI does a great job with trying to get news out in terms of what's happening in terms of new drugs or therapies. You can reach out to any of us at SCRI; we're happy to help as well. There are a lot of avenues that [oncologists] can use to better understand the available options.

Forming a multidisciplinary clinic or establishing multidisciplinary rounds can be helpful when addressing more challenging cases and ensuring that all options are considered.. It's important to have radiation, medical oncology, and urology all working as a team. Developing relationships with colleagues who treat these patients and establishing a regular time to review cases can be a good place to start. Over time, more patients may be discussed at these conferences, making the collaboration increasingly productive.

What are your final thoughts on the current state of prostate cancer treatment?

It's a really exciting time in prostate cancer, and the therapies are advancing rapidly. It's important to remain hopeful and to explore options. From a patient standpoint, it's OK to ask for second opinions. It's OK to explore clinical trials. Some of these things that are in studies are probably even more promising sometimes than what we're seeing currently, just because we've been developing these drugs for a number of years. We’re always trying to look at better resources for patients, as well as finding more and more trial options.

REFERENCES

1. Attard G, Agarwal N, Graff J, et al. Phase 3 AMPLITUDE trial: niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. J Clin Oncol. 2025;43(suppl 17):LBA5006. doi:10.1200/JCO.2025.43.17_suppl.LBA5006

2. Fizazi K, Clarke NW, Santis MD, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol. 2026;37(1):53-68. doi:10.1016/j.annonc.2025.10.004

3. Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798

4. Tagawa ST, Sartor O, Piulats JM, et al. Phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Presented at: ESMO Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA6.