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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.

The PROfound trial is a recent example, said Simon Van Wambeke, MD, of ZNA (Hospital Network Antwerp) Jan Palfijn in Belgium, and colleagues. The trial included patients with metastatic castration-resistant prostate cancer (mCRPC) with a mutation of a predefined set in a DNA repair gene that had progressed on at least one androgen receptor targeting agent (ARTA), enzalutamide or abiraterone. Patients in the experimental arm received a poly (ADP-ribose) polymerase inhibitor, olaparib, and patients in the standard-of-care arm received a physician's choice treatment.

However, the authors said, "the labeling of the control arm as treatment of physician's choice was misleading, because the physician's choice was limited to only abiraterone or enzalutamide, antihormonal treatments that patients had already progressed on before enrollment," the team wrote. "Moreover, almost 20% of patients had already been treated with both of these agents."

Thirty-five percent of patients had not received prior docetaxel, and 45% of docetaxel-pretreated patients had not received prior cabazitaxel -- treatments proven to improve survival in the mCRPC setting.

"Thus, 20% of the patients in the control arm received a treatment that was effectively a placebo with adverse effects (ARTA after progressing on both ARTAs), and 80% were denied an effective taxane chemotherapy," the authors wrote. "For registration trials aiming to establish a new treatment, the new drug should be tested against the best standard of care, and not the minimum treatment that passes as acceptable."

In the following interview, Van Wambeke discussed the prevalence of this problem, the potential harms to patients, and ways to address it.

You performed a literature search to assess the prevalence of this problem. What did you find?

Van Wambeke: First of all, we were surprised that some published and ongoing trials use sequencing of ARTAs like enzalutamide or abiraterone as a control arm when this strategy has been discouraged for some years by guidelines because of the lack of efficacy. At the time we wrote the article, we searched clinicaltrials.gov for an ARTA-ARTA control arm in actively recruiting phase III mCRPC trials and found that almost one in three used it (we excluded trials where only chemotherapy-ineligible patients were recruited).

In fact, there were almost no phase III trials randomizing against cabazitaxel or radium-223, both of which have demonstrated a survival advantage for men with mCRPC -- the academically sponsored European ProBio trial being an exception.

Could this practice be harmful to patients included in substandard control arms?

Van Wambeke: We think so, because it may deny patients effective treatment. For example, we know cabazitaxel is more effective than ARTA after docetaxel and a first ARTA from the CARD trial. Secondly, it may also be harmful to many more patients outside of the trial because it makes adequate analysis of efficacy of the experimental arm impossible, impeding rational use of an (almost invariably) expensive new treatment option. Lastly, ARTA-ARTA(-ARTA) sequencing may be seen as a good treatment option by our colleagues given that it was used as standard of care in phase III trials.

Should oncologists try to avoid referring their patients to clinical trials with such substandard control arms?

Van Wambeke: I would rather not include a patient in such a trial, but I'd prefer clinicians not to be faced with such a question, given the ethical, scientific, and regulatory problems associated with this; also the Declaration of Helsinki forbids substandard control arms.

How can this problem be fixed, and is anything being done at present to address it?

Van Wambeke: Substandard control arms in trials are a problem larger than the mCRPC setting and are seen all across medicine. How to address this at all levels is beyond my capacity to address. I think we should start by raising awareness of this problem to all stakeholders of clinical trials.

In this vein, a recent editorial by major clinical trialists in the prostate cancer field is encouraging. As oncologists, I think we should discourage the design or execution of trials that include substandard control arms.

Read the study here and expert commentary about the clinical implications here.

Van Wambeke reported relationships with Roche, Janssen-Cilag, and Ipsen.

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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