Alicia Morgans: Hi. My name is Alicia Morgans and I'm a GU medical oncologist at the Dana-Farber Cancer Institute in Boston. I'm so excited to have here with me today, Dr. Alfredo Berruti, who is a GU medical oncologist and professor at the University of Brescia in northern Italy. Thank you so much for being here with me today.

Alfredo Berruti: It's a pleasure for me.

Alicia Morgans: Wonderful. I am really excited that you and the team presented some excellent work at GU ASCO 2022, thinking about how we can best care for patients with adrenocortical carcinoma. Can you tell us a little bit about it?

Alfredo Berruti: Yeah. As you know very well, we are dealing with an extremely rare disease that is affecting about 0.72 new cases per million population per year in Western countries, so an exceptional disease. This disease is usually aggressive and surgery is the mainstay of therapy. However, due to its rarity, the first diagnosis is often delayed, and therefore, surgery is only performed in about 50% of patients. Even radical operated patient with adrenocortical carcinoma are at high risk of relapse, and retrospective surgical series have shown that the proportion of relapsing patient is between 40% to 70%, so high proportion. Therefore, there's a strong rationale for adjuvant therapies. Actually, currently, the international guidelines recommend mitotane, that is the referent drug for this disease, is the DDT derivative, we know this drug for many, many years. This drug is currently recommended in radical operated patient that are at risk, high risk, of relapse. For patient with low risk, the decision is left on the multidisciplinary team taking into account of the cost benefit ratio.

The ADIUVO trial was designed to demonstrate the potential efficacy of mitotane administered in adjuvant [inaudible] and in radical operated patients with adrenocortical carcinoma that were at low, intermediate risk of relapse, meaning stage one to three, or zero, and Ki-67 less than 10% in neoplastic cells. This trial was a big effort because it involved almost all the referring centers for these extremely rare disease in the world.

The plan [inaudible] precise was 200 patients to be enrolled; 100 for each treatment arm. But, unfortunately, after 10 years actual, we only recruited 91 patients, about half of the plan that patient to be enrolled. In 2018, we decide to stop the trial, to close the trial, and analyze the data. Due to the low accrual rate in 2011, we introduced a parallel study, the ADIUVO OBSERVATIONAL, in which we included patients, that for any reason, for patient or physician decision, did not enter the ADIUVO trial, but follow it only. We have two court to follow prospectively, and from 2011 onwards, the patient had the possibility to choose to be randomized and participate trial and receive mitotane, or observation on the base of the random, or to decide the treatment to be observed or mitotane.

So to enter the ADIUVO OBSERVATIONAL, and the results substantially fail to demonstrate superiority of adjuvant mitotane with respect to observation in terms of relapse survival and overall survival. But it should be noted that the patient population, selected according to the eligibility criteria of the ADIUVO trial, unexpectedly show good prognosis and the relapse was 25% in the placebo arm. This is an unexpected finding and good news for the patients. So patients enrolled in the ADIUVO trial have a relative good prognosis and may not need adjuvant mitotane although, as you can easily understand, the few number of patient enrolled and the limited events prevent us to give a fine statement, a firm conclusion. But on the basis of the result of this trial, of course we couldn't recommend in a routine basis, adjuvant mitotane. This is also an important step further because before this study, we have no possibility to select patients to address a adjuvant therapy or observation.

Alicia Morgans: Well, I first want to really congratulate you and the team for persevering for 10 years to enroll these patients. Because as you said, and as we discussed before we started filming, this is a very rare cancer, especially if we're trying to enroll people who sometimes can be quite sick, but it's a variable presentation. And then to randomize them in this, the whole process is quite an undertaking and quite a labor of commitment and love by you and the team. So congratulations there. And it's interesting, and in very important to see that the control arm did better than we expected. And then also very interesting to see, that we didn't see, that mitotane actually added any benefit to that. So what are your thoughts on why? Do you think that it's solely because it was underpowered from the original design? Was it because the patients did better than expected overall? What was driving this?

Alfredo Berruti: I think that both are the reason why the study substantially failed to demonstrate a benefit. Of course, on the basis of this study, we should be careful to prescribe mitotane in this patient population. Because as you know, mitotane is quite toxic, although tolerable, but it's also challenging to manage. It requires experienced physicians. We have to manage the hyposuprarenalism and the other side effect typical of the drug. So if the patient could avoid such a toxic therapy, it could be a good undoubted, a good news. Fortunately, we observe in the follow-up only seven death, and two of them not related to the disease. So only five deaths were disease related. And this is another interesting observation underlining that this patient population is a proxy estimate to have a relative good prognosis. And this is, I think, the most relevant results of this trial, because it is also confirmed in the parallel trial ADIUVO OBSERVATIONAL that showed the same results as ADIUVO randomized.

Alicia Morgans: Wow. So I think the bottom line, if I understand correctly, is that surgery remains the mainstay of the approach to treating adrenocortical carcinoma. And that mitotane really may have limited use in this regard until clinical trials demonstrate otherwise, whether it or something else adds some benefit.

Alfredo Berruti: Yeah, but when we are dealing with patient with high risk. A patient with high risk are expected to recover frequently. In this patient population, we observed a reduction in that rate and progression rate. Although we don't have randomized clinical trial, we only have retrospective series, case control study. One of them was published in 2007, [inaudible] medicine, but still remain a retrospective study. But the other ratio of all retrospective [inaudible] as homogenous, there, was no heterogeneity among the other ratio. Therefore, in patient with high risk of relapse, mitotane, we are all convinced, is helpful.

Alicia Morgans: Absolutely. So very, very clearly benefit in the high risk population, but in this lower risk population, it is good to know that we do not need to expose patients to this very difficult to manage, and you put it lightly, very difficult to manage treatment. So I want to commend you and the team yet again, and just thank you for contributing this and saving patients the exposure to this treatment that they don't need. I think that's a really important contribution and I sincerely appreciate your time and your expertise in talking with us today.

Alfredo Berruti: Thank you so much.