<p>Despite the availability of docetaxel and ARPIs for metastatic hormone-sensitive prostate cancer (mHSPC), their use in combination with ADT remains suboptimal. Our featured experts explore the classification of metastatic disease volume, the role of genomic biomarkers, and barriers to implementing combination therapies.</p>

“High-volume metastatic disease” is defined as the presence of visceral metastases and/or 4 or more bone metastases with at least 1 outside of the vertebral column and pelvis, and it was a criterion used in the CHAARTED study. I personally do not think that the determination of high-volume disease should be based on a prostate-specific membrane antigen positron emission tomography (PSMA PET) scan. I always like to see computed tomography (CT) and bone scans to determine whether a patient has high-volume metastatic disease because PSMA PET scans are so sensitive, and the CHAARTED study did not determine high-volume status based on PSMA PET scans. I also think that we need to obtain tumor genomic sequencing. Even though we do not have prospective data, I have a lower threshold to add docetaxel to the ADT-plus-ARPI therapy backbone if a patient has a low expression of RB1, PTEN, and TP53 (or at least 2 of them) in their tumor. This is an area that is going to be evolving very rapidly over the next several years.

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Despite docetaxel having consensus approval for use in this space since the CHAARTED study, and despite the fact that ARPIs have been available since 2018, fewer than half of patients with mHSPC receive combination therapy with ADT plus ARPI therapy and/or docetaxel. It is getting better, but it should be unacceptable to see fewer than 80% to 90% of patients receive SOC therapies. In a recent implementation study, when we looked at which clinicians were less likely to prescribe SOC combination therapies vs ADT monotherapy, those who were satisfied with a 0% to 49% decline in prostate-specific antigen (PSA) level were less likely to use the SOC. Clinicians who knew that the goal should be a PSA reduction of 75% to 100% for all patients, regardless of baseline PSA, were more likely to start combination therapy.

Following the CHAARTED study, we were left with a very imprecise definition of high-volume disease. Conventional imaging has a role, but I do not think that we need to perform it in a patient with metastatic disease that was confirmed by a PSMA PET scan to determine whether they have high-volume disease as defined by the CHAARTED criteria. I like to say that the extent of metastatic disease should be but 1 predictor of cancer-specific mortality, so we want to look at other factors. I think that we are going to increasingly use molecular biomarkers to define patient subgroups who are likely to benefit from chemotherapy. Hopefully, in the future, the traditional definition of high-volume disease by conventional imaging will become a minor—and perhaps unimportant—part of our decision making regarding systemic therapy.

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I think that there are 2 big reasons for the slow adoption of combination therapy, although neither is very defensible. First, some early studies may have led to the view that treatment intensification was only for patients with the worst prognosis. Although subsequent studies of ARPIs have shown that the benefit is conferred across all risk groups, I think that it has taken a while for the community to catch up. The second reason is the gross misunderstanding that patients may do just as well if you save the ARPI for when they progress to metastatic castration-resistant prostate cancer. Despite the fact that the control groups of these trials had very high rates of crossover to subsequent ARPI therapy, there was still a consistent overall survival benefit that negates this argument. When I meet a patient with de novo metastatic prostate cancer, I will start them on 2 treatments (ie, ADT and ARPI therapy) and obtain tumor genomic testing; when they return for follow-up, we will make the decision on whether a third drug is necessary.

I find it interesting that many clinicians have the philosophy of starting patients on ADT first and waiting a while before starting them on an ARPI. My concern about this is that it becomes forgotten by the clinician. For clinicians who say that they start patients on ADT and then will see them back in a couple of months, I get the idea that they might not actually pull the trigger for the ARPI if the patient has a good PSA at their follow-up visit.

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For patients with newly diagnosed metastatic prostate cancer, I like to get them started on an ARPI the same day they start ADT, if possible. I have samples available, and, while I do not think that you have to do this, it means that I will know that patients are going to get treatment right away and it helps set the tone that single-agent treatment is not enough. For urology groups that have their own self-dispensing pharmacy through the Large Urology Group Practice Association (LUGPA) program, there should not be any excuses for patients not to start an ARPI the same day they start ADT. If a patient is a candidate for docetaxel therapy based on PSMA PET, I will partner with genitourinary medical oncology as well.