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Several new anticancer drugs have been approved on the basis of clinical trials that used substandard control arms, and this problematic practice is continuing, noted authors of a recent "Comments and Controversies" article in the Journal of Clinical Oncology.

In this exclusive MedPage Today interview, Eric A. Klein, MD, chair of the Glickman Urological and Kidney Institute and professor of surgery in the Lerner College of Medicine of the Cleveland Clinic, offers his takeaways on the trials discussed in the article.

The following is a transcript of his remarks:

I'm Eric Klein, the emeritus professor and chair of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Today, I'll be discussing a commentary published recently in the Journal of Clinical Oncology that tackles the thorny issue of how best to define the standard of care arm in clinical trials, in view of practical concerns of what might be called doability, in successfully recruiting patients for randomization.

Randomized clinical trials [RCTs] that compare standard of care to new treatments are of course critical in advancing patient outcomes. On the other hand, a well-designed RCT that fails to meet its accrual goals adds no value to patient care.

The challenge here is to design trials that ask and answer meaningful questions in ways that can be successfully performed. Clinical trials in advanced prostate cancer are especially relevant to this debate, because there are so many treatment options with varying toxicity, ease of use, and variability in application in community practice.

In the commentary, the authors observed that several prominent trials for advanced castrate-resistant prostate cancer used what might be considered nonstandard of care comparators to the experimental treatment arm. Both trials showed improvements in overall survival for the experimental arms, but the thrust of their argument is that both trials used ineffective therapy in the control arm.

To support that claim, they cite ample data for the trial-eligible populations that use of a second AR [androgen receptor] blocker after progression on a first AR blocker has very low objective response rates and do not prolong survival, while taxanes have been proven to do so.

Let's look at each trial in detail. In the PROFOUND trial, which tested the PARP inhibitor olaparib in patients with DNA repair defects, men who had progressed on at least one androgen receptor blocker were randomized to olaparib versus switching to a different AR blocker, despite the fact that 20% of patients in the trial had already been treated with both abiraterone and enzalutamide. They also pointed out that the control arm prohibited the use of a taxane, which has been shown to prolong overall survival in men meeting the criteria for study entry.

In the VISION trial, where eligibility was defined by progression after an AR blocker and one or two cycles of a taxane, the experimental arm consisted of treatment with the radioligand 177Lu-PSMA-617. In this trial, the control arm prohibited additional chemotherapy, even in men who had only received one cycle previously.

In effect, the control arm also was one again of sequential AR blockade, despite that almost 50% of patients had already received and progressed after two AR blockers. They correctly point out that men who entered this trial could have received cabazitaxel, which has been shown to improve overall survival in men who meet eligibility for the trial.

The authors go on to highlight four ongoing trials that use the same sequential AR blocker strategy in their control arms.

So what can be made of all of this? Are the results of PROFOUND and VISION valid? Can it really be concluded that the experimental arms were superior to standard of care?

I believe the authors correctly point out the flaws in the study designs, which consign patients in the control arms to commonly use the relatively ineffective therapy while denying them the potential benefit of taxane chemotherapy.

On the other hand, switching to another AR blocker after progression on an initial one is commonly used in the community because it's easy and desired by patients. Rightly or wrongly, patients generally prefer an oral agent as they're well tolerated, the occasional patient has a meaningful clinical response, and there is the feeling that chemotherapy can be used as a last resort.

So we are left with the question, what defines standard of care? Is it defined by the more toxic therapy that has proven to prolong overall survival? Or is it defined by what is most available to patients and commonly used in the community, and thus facilitates the successful completion of important clinical trials that test new therapies?

The author suggests that according to the Helsinki principles that patients in the control arms of PROFOUND and VISION were actually harmed by being denied the option for chemotherapy that has proven to prolong overall survival.

What the authors overlook in my view is that patients have a choice of how to be treated. And that choice includes an informed decision to participate or not in a clinical trial of an unproven therapy. The expectation is that during the informed consent process for these trials, they were offered the option of chemotherapy as standard of care, versus participating in a trial that did not include that option and had a 50% chance of getting an unproven therapy.

Viewed in that context, I do not believe patients were harmed by participation in these trials. I conclude with the observation that we should never overlook the idea that a patient's values are always the most important consideration in their care.

Read the review here and an interview about it here.

Source Reference: Van Wambeke S, et al "Controlling the control arm in metastatic castration-resistant prostate cancer trials: Best standard of care or the minimum standard of care?" J Clin Oncol 2022; 40: 1518-1521.

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