When I look at the utilization of combination therapy for our patients with both low- and high-volume mCSPC, I observe underutilization and undertreatment. The CHAARTED trial, as well as multiple arms of the STAMPEDE, ARCHES, ENZAMET, TITAN, and ARASENS trials, have all clearly demonstrated the benefit of combination therapy over androgen deprivation therapy (ADT) monotherapy for patients with mCSPC. All of the contemporary guidelines reflect this standard, yet, in the United States and globally, many urologists and medical oncologists still only seem to be utilizing ADT monotherapy, which is classic undertreatment. This is an issue that must be overcome soon. 

There is evidence for undertreatment in mCRPC as well. There are at least 6 distinct mechanisms of action and many more novel treatments for mCRPC, but data suggest that, on average, patients are availed of relatively few of these treatments before they succumb to mCRPC. If a patient is going to succumb to the disease, does it not seem appropriate that the individual receive as many novel mechanisms of action as possible or enroll in a clinical trial? Further, the sequencing of 1 novel hormonal agent after another is an inefficient strategy. Data from the PROfound, CARD, and PLATO trials, along with the recent VISION trial, suggest that we should be treating patients with therapies that have differing mechanisms of action.

Regarding the overtreatment of prostate cancer, there are several areas to highlight. More patients who have grade groups 1 and 2 localized prostate cancer could probably be undergoing active surveillance. Additionally, we have overutilized testosterone suppression, historically. In biochemical relapse, the decision to initiate testosterone suppression must be weighed very carefully, as there are many trade-offs and side effects associated with testosterone suppression.

This is a particularly important topic now in the context of prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging. We are transitioning from a conventional imaging paradigm to a next-generation imaging paradigm. And, with that transition, there is the potential for both under- and overtreatment. 

PSMA PET imaging has the potential to provide important clinical information in the setting of prostate-specific antigen (PSA) progression following definitive local therapy. It is also useful in patients with high-risk local disease in the detection of occult metastases. In the mCRPC setting, PSMA PET is performed in consideration of radioligand therapy with lutetium Lu 177 vipivotide tetraxetan. The VISION trial, which led to the recent US Food and Drug Administration approval of lutetium Lu 177 vipivotide tetraxetan, required PSMA-positive disease using Ga PSMA PET/computed tomography.

Despite this important development, we need to remember that when we try to apply findings from newer, more sensitive imaging for patient management decisions, we do so in the setting in which all of our current therapeutics were developed in studies using conventional bone scan and computed tomography imaging, creating the potential risk of both under- and overtreatment. In a patient with biochemical recurrence and some equivocal findings on PSMA PET, not offering curative-intent salvage therapy (eg, prostate bed radiation therapy plus short-term ADT) raises concerns about undertreatment. In contrast, in patients with biochemical failure and no overt metastases on conventional imaging but with equivocal findings on PSMA PET, introducing therapies and toxicities earlier than what we would have done in the past raises concerns about overtreatment. 

I agree with Dr Dreicer that, largely, PSMA PET imaging could complicate how we categorize patients in earlier disease stages, and that more data are needed in those settings. Additionally, as Dr Shore noted, it seems that the standard of care for treatment intensification in mCSPC has not necessarily translated well into clinical practice, and I do believe that there is considerable undertreatment of both mCSPC and mCRPC.

Regardless of the disease setting that we are aiming to treat, I think that we all consider the patient’s life expectancy, baseline status, and comorbidities as factors that are very relevant to the risk of over- and undertreatment. And there is a need to consider age-associated comorbidities in addition to chronological age to ensure that we do not have an inherent bias that prevents us from applying level-1 evidence to older individuals.

Some clinicians might be hesitant to recommend newer intensification strategies for a patient who is advanced in years. Consider an 80-year-old man with mCSPC. If he is very healthy and has a 10-year life expectancy, he would absolutely benefit from treatment intensification, and it should be offered to him. Conversely, if he has severe comorbidities, treatment intensification might carry a risk of overtreatment, since even the relatively well-tolerated androgen receptor–targeted agents can have negative interactions with certain chronic conditions.

As Dr Dreicer alluded to, there can be uncertainty with nonmetastatic CRPC on conventional imaging in view of equivocal findings using next-generation imaging. PROSPER, SPARTAN, and ARAMIS were large, placebo-controlled, phase 3 trials that showed a significant benefit in metastasis-free survival in men with nonmetastatic CRPC, as determined using conventional imaging, and all 3 trials selected patients based on short PSA doubling time. In this case, I think that the use of PSA doubling time to select patients for therapeutic escalation really highlights the need to incorporate prognostication when we are applying clinical trial data to the patient before us.