The detection of metastases is a defining event in metastatic castration-sensitive prostate cancer (mCSPC), with the standard of care being to offer patients continued androgen deprivation therapy (ADT) plus chemotherapy or a second-generation antiandrogen. This standard has been evolving, and the Medicare database (January 2009–December 2018) analysis presented by Daniel J. George, MD, at this year’s ESMO Congress was noteworthy, as the findings were surprising (abstract 616P). Researchers examined the real-world use of advanced therapies by metastatic site (eg, viscera, bone, or lymph node only) and age group (<75 years and ≥75 years) in patients with mCSPC. What was unexpected was that, even for the most recent period (2017-2018), approximately three-quarters of all patients were treated with ADT alone, while less than 5% received ADT plus docetaxel. This was after offering docetaxel and/or the novel hormonal therapies in addition to ADT became standard and rates were low. The more contemporary patients did have more exposure to chemotherapy, which was a positive sign, and those with visceral and bone metastases were more likely to undergo treatment intensification, as were patients who were younger than 75 years of age; however, overall, this was not a very good report card. 

We know from the CHAARTED trial that survival can be extended by more than 1 year in some of these patients by adding chemotherapy to ADT. The STAMPEDE study, which was conducted in Europe, had a similar design and showed benefits with abiraterone in addition to primary ADT in both low- and high-volume patients. In CHAARTED, more patients had progressive mCSPC, while in STAMPEDE, more had de novo mCSPC, so there may be differences in the disease biology. Nonetheless, in looking at the most common use scenarios in a Medicare data set (ie, abstract 616P), I would have expected to see more patients with visceral metastases being offered chemotherapy and more patients without visceral metastases (ie, lower-volume disease) being offered the novel antiandrogen therapies. Our hope is that we will continue to see improvements in the real-world utilization of life-extending, advanced therapies, with growing recognition that ADT alone is no longer the standard of care for metastatic prostate cancer. There are always going to be exceptions in which primary ADT is the only therapy that a patient would be able to receive, so we do not expect to see layering on top of ADT in 100% of cases, but, in general, most patients should be offered additional therapy so that they have the opportunity to have those survival benefits. 

The role of prostate-specific membrane antigen (PSMA)–based imaging in patient selection for targeted radioligand therapy is essentially a new frontier for us. As a biomarker in prostate cancer, PSMA expression is fairly ubiquitous. Some patients have tumors that do not express PSMA, but it is unclear whether PSMA avidity on positron emission tomography imaging would be needed to identify patients who might benefit from PSMA-targeted radioligand therapy. 

Patients in an unselected population appeared to respond to lutetium-177–PSMA-617, as noted in a poster presented by Scott T. Tagawa, MD, MS, FACP, at the ESMO Congress 2021 (abstract 600P). There are likely PSMA-expressing circulating tumor cells and small deposits of tumors that are below the threshold for detection by imaging. And so, benefits can be observed in the absence of radiographic confirmation. 

Additionally, as noted in abstract 5770, in the setting of lutetium-based combination therapy, you might not necessarily need a lot of PSMA expression to have an impact. This was in reference to an early phase study of lutetium plus pembrolizumab. It could be something like a one-two punch, since, when you combine therapies, some of the tumor cells are destroyed and others are exposed so that their antigenicity may be more robust. The benefits of the combined approach are still theoretical, and this trial was in its early days at the ESMO Congress 2021, so we will have to wait to see the results.