The Role of Genetic and Molecular Testing in Treatment Selection for HSPC

At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, a roundtable of expert panelists convened to discuss the latest research and practice updates related to metastatic hormone-sensitive prostate cancer (mHSPC). Dr. Tanya Dorff of City of Hope Comprehensive Cancer Center was joined by Drs. Dan Childs, Andrew Hahn, Cora Sternberg, and Vadim Koshkin in the discussion.

In the second part of the roundtable, the panel goes in-depth on the use of SBRT as metastasis-directed therapy in newly diagnosed prostate cancer, the role of genomic and germline testing in treatment decisions, prognostic tools beyond disease volume, and the impact of symptoms such as bone pain on treatment intensification.

View the next segment on Navigating ADT Choices: Agonists Versus Antagonists and the Role of AR Pathway Inhibitors.

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Dr. Dorff: Tell me a little bit more about your approach to using SBRT as metastasis-directed therapy in a newly diagnosed metastatic patient.

Dr. Hahn: When considering de novo metastatic disease, particularly in lower-volume cases, I am generally hesitant to use SBRT if there are too many metastases. Radiation oncologists can treat more than four or five lesions, but when I see that many, I tend to lean towards systemic therapy and possibly radiation to the prostate instead. However, when I encounter a patient with a single metastasis, particularly in the pelvic bone, I seriously consider metastasis-directed therapy, especially if confirmed on a PSMA PET scan.

The key consideration for me is whether I can ultimately limit the duration of hormone therapy, aiming for a finite period of around two years rather than indefinite treatment. In these cases, if I incorporate metastasis-directed therapy, I feel more confident about stopping hormonal therapy at the appropriate time. However, there is a significant difference in the level of supporting data when comparing de novo cases to metachronous recurrences. Most studies, such as STOMP and ORIOLE, focused primarily on patients with metachronous, biochemically recurrent prostate cancer. There is less data available for guiding treatment in the de novo setting.

Dr. Dorff: Dr. Koshkin, do you utilize genetic testing, either germline or somatic, to guide your treatment choices?

Dr. Koshkin: In the hormone-sensitive setting, genetic findings influence my decisions to some extent. For example, certain genomic markers like SPOP mutations indicate potentially more favorable disease progression. While I would not necessarily avoid treatment intensification based on this, I might be less inclined to use triplet therapy.

Conversely, patients with BRCA mutations may not require immediate changes to their therapy in the hormone-sensitive stage, but those mutations signal a higher risk of aggressive disease and the possible need for additional treatments later. Upcoming clinical trials may further refine our approach to hormone-sensitive disease based on these genetic insights.

Dr. Hahn: I would like to add a few additional prognostic tools to the discussion. We frequently focus on disease volume, and while genomic data is valuable, there are other important clinical indicators.

For instance, the number of metastases alone does not always determine aggressiveness. If a patient has six metastases but a PSA of only two and a Gleason grade group of five, I would reassess the entire case. Additionally, molecular markers such as early loss of multiple tumor suppressors, particularly RB1, PTEN, and TP53, indicate a more aggressive disease biology. If a patient has lost two or more of these suppressors, I would be significantly more concerned.

Dr. Sternberg: Typically, we identify these molecular alterations later in the disease course, after patients have already been on androgen deprivation therapy for a while. They are less common at the initial metastatic hormone-sensitive stage.

Dr. Hahn: I agree; they are rarer in the initial setting, but I have occasionally encountered them early on.

Dr. Sternberg: One important takeaway from the NCCN guidelines is the recommendation that all patients with mHSPC undergo both somatic and germline genetic testing.

Dr. Dorff: How does the presence of pain influence your treatment approach? If a patient presents with only a few metastases but experiences significant bone pain, do you interpret that as a different disease biology?

Dr. Childs: When a patient is symptomatic at presentation, I am more inclined to pursue treatment intensification early. Dr. Alicia Morgan has done excellent work analyzing prior clinical trial data, which suggests that symptoms can help identify patients who might benefit from early chemotherapy.

My approach aligns with what has been discussed; patients with substantial disease burden or significant symptoms, particularly if there is a discordance between PSA levels and the extent of disease, are candidates for early chemotherapy.

I am also very interested in how genomics can further refine decision-making, though we are not quite there yet. That said, germline testing remains crucial early in the disease course, not only for treatment planning but also for family members. If a patient has a BRCA2 alteration, cascade testing could impact their relatives’ cancer screening and risk assessment.

Dr. Dorff: What are your thoughts on the Decipher genomic classifier data presented at ESMO, particularly regarding its application in metastatic prostate cancer and its potential role in predicting response to docetaxel?

Dr. Sternberg: I found it intriguing. At our institution, we primarily use Decipher for patients with biochemical recurrence to help determine whether to treat them for six months versus two years. However, there is still limited data in this setting, and factors such as the presence of cribriform histology or Gleason 5 disease also influence treatment duration. While we frequently use Decipher in these contexts, I have never employed it to predict chemotherapy response. The ESMO presentation was certainly thought-provoking.

Dr. Dorff: It will be interesting to see if future prospective studies validate these findings. One notable aspect is that a genomic signature originally developed for localized prostate cancer appears to retain prognostic value in the metastatic setting. However, what stood out was that Decipher seemed to predict benefit from docetaxel but not from abiraterone. Moreover, this distinction held across both high- and low-volume disease, which is significant since volume has traditionally been one of our strongest clinical predictors.

Dr. Childs: That is an interesting point. AR pathway inhibitors show benefit regardless of disease volume or whether the cancer is metachronous or synchronous. However, Decipher appears to differentiate chemotherapy response, which is intriguing. My baseline approach for metastatic hormone-sensitive prostate cancer is to start with androgen deprivation therapy plus an AR pathway inhibitor, then decide whether to add chemotherapy based on additional factors.