Dr. Eleni Efstathiou is an Associate Professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, Texas.

She spoke with Prostatepedia about her clinical trial combining Erleada (apalutamide) with Zytiga (abiraterone).

What is the thinking behind your trial combining Erleada (apalutamide) with Zytiga (abiraterone) in men with metastatic castrate-resistant prostate cancer? Why this combination as opposed to another?

Dr. Efstathiou: Here is the idea. There is a large trial on combining Zytiga (abiraterone) and Erleada (apalutamide) for all patients who have failed original Lupron (leuprolide) injections or standard androgen deprivation therapy. This trial is for men with metastatic castrate-resistant disease; it compares that combination to just one of the agents alone. I’m part of the steering committee for that international trial.

The trial that I just initiated here at MD Anderson is a smaller trial. This trial is trying to identify and confirm a subset of men who harbor cancers that are going to be exquisitely sensitive to the combination and may need no further treatment for years and not just an average of about a year

This all started with my first trial, now 11 years old. That specific trial was characterized by the fact that the men who received Zytiga (abiraterone) underwent biopsies of their bones while on treatment so I could study what was going on in the cancer realtime. It showed me that 70% of the men would respond. There was a reaction in the cancer cell while the androgens were dropping and they were undetectable. Their androgen receptors were going up. The next trial that I did used a drug that is very close to Erleada (apalutamide) called Xtandi (enzalutamide). That trial showed exactly the inverse, that as you gave that drug the receptor was switched off, but the androgens went up. All of this is in the tumor cells. This means there is some feedback happening, but does this feedback contribute to resistance? Could the combination actually help these men who get both drugs survive longer and get better responses?

But there is a caveat. I looked more carefully to find the characteristics in the tumor samples taken prior to treatment and found that there were specific molecules that, if expressed, were associated with a benefit. It made sense to me to focus on those specific characteristics in the cancer and try to combine.

I then did another trial where I combined Zytiga (abiraterone) and Xtandi (enzalutamide) and looked to see if my theory made sense. It did. It looked like the men who had these molecular characteristics responded better on the combination than those who didn’t.

But that was all hypothesis. The next thing you need to do when you discover something is test it. Then you need to confirm it to validate it. I used a 180-patient trial to test it. The next step would be the validation if testing looked promising. A validation means you have preset the parameter of the research trial; you’re trying to become agnostic to the outcome so you’re not biased in any way.

The testing also panned out. The trial we’re now discussing is the validation. Patients who come in the door accept to undergo a biopsy. We don’t need to do the old-school bone marrow biopsies anymore. We have great radiologists who go in with very fine needles and take several samples so the patient has no pain, just the discomfort of the process. Then we look at the cancer cells to see if they have these characteristics. I would tell you that about 30% of the cases have these characteristics that would make them eligible for the trial. The men who do have these characteristics in their cancers start treatment. If my hypothesis is correct, the validation will be that 90% of these men should respond in an outstanding and protracted fashion. I’m trying to hone in on who would be the ideal candidate for a combinatorial trial. The way the field is going, we’re throwing all the drugs at all patients; that helps a lot of people to a degree, but on the other hand, it causes a lot of toxicity, especially if you combine two rather than one agent. That is the main gist of this trial.

What can men expect to happen step by- step?

Dr. Efstathiou: You get a biopsy. In about a week, we tell you if you area candidate or not. You start the treatment. Then it’s quite straightforward: we follow you just as you would be followed in your doctor’s office. You come once a month to see me. This may go on for years, if all goes well. I have some patients who have been on treatments like this for years. Sometimes after six months of treatment, apart from seeing us to evaluate toxicity, we also perform imaging again to see what is going on with the cancer.

What images studies will you be using?

Dr. Efstathiou: CT scans and bone scans. We have not included, unless it’s needed for this trial, more advanced imaging such as PET scans. As we monitor these imaging studies, we see how the cancer cells seem to be more quiescent. The lesions become smaller. If, God forbid, the disease tries to progress again, then we would repeat a biopsy Remember, as I’m sure you’ve discussed with a lot of other specialists in prostate cancer, one of the main concerns is prostate cancer’s heterogeneity. When I’m doing biopsies, I’m actually looking at a snapshot of a specific subset of cancer cells. What if there is a cohort of cancer cells in there that is very resistant and expresses completely different molecules?

This clinical experiment gives me the opportunity to see if the way I am assessing things is actually capturing well what is happening with regard to the prostate cancer activity. There are a lot of investigators out there who are huge advocates of liquid biopsies without having done the basics of assessing what is going on in the actual tumor that has grown in the bone, lymph nodes, or liver. I understand that the dilemma for most people is the difficulty of doing biopsies, but if we want to be honest in all other malignancies, that’s how the development of all the targeted agents started. At the end of the day, it is going to be important to not ignore the actual tumor samples and to try and characteristics those well. Above and beyond this specific trial, one of my main efforts is to hone in on a classification of the disease that allows you to appropriately designate specific treatments to specific patients. There was some nice work recently presented in a meeting that supports that idea. Some of the mutations or alterations can be found early on.

If we know which these are, then we can pursue them. If we know that others change over time, then we can do real-time biopsies.

Which tumor biomarkers are you looking at?

Dr. Efstathiou: One of the most important parameters is androgen signaling. I was the one who reported for the first time the association of AR-V7 in the tumor sample with lack of response to these drugs. Right after that came the liquid sample data from the Johns Hopkins and Memorial Sloan Kettering groups who were doing it in the circulating tumor cells.

One of the markers is related to AR-V7, but I went a step further. The androgen receptor needs to be intact. I’m looking at the two ends of the androgen receptor. The one end is the end where the androgens go and attach themselves. The other end is the stable end, the one that never changes. The end to which the androgens attach themselves is the one that is affected by mutations and variants. I measure both ends and then I look at the difference in the ratio between the two. That’s another important marker.

I also look at PTEN, which is a very known marker. I look at RB loss, p53 mutation, and the proliferation index of the cancer.

What are the eligibility criteria?

Dr. Efstathiou: It’s very simple. Patients must have not received previous new agents such as Zytiga (abiraterone), Xtandi (enzalutamide), or Erleada (apalutamide). They must have failed standard hormonal approaches, such as androgen deprivation therapy or bicalutamide. They also have to have metastatic disease. These are the main criteria. It’s very straightforward.

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Non-metastatic castrate-resistant prostate cancer (nmCRPC) is a clinical state in which a patient on androgen-deprivation therapy (ADT) has a rising PSA but there are no radiological findings of metastases on CT or bone scan. Management of nmCRPC is evolving quickly, but it is a field in which there have been recent drug approvals amid a strong and growing interest in keeping patients metastasis-free for as long as possible. About 10-20% of prostate cancer cases are castrate-resistant, but nearly 16% of those castrate-resistant patients have no evidence of metastatic disease at the time their castrate-resistance is diagnosed.

Not all nmCRPC disease is the same. For some patients, observation is a viable option; for other patients—especially those with a PSA doubling time of less than or equal to 10 months—randomized Phase III clinical trials have shown a benefit and an increase in metastasis-free survival with the use of Xtandi (enzalutamide) or Erleada (apalutamide). New imaging techniques on the horizon may also be very helpful in assessing nmCRPC patients.

In February 2018, the FDA approved Erleada (apalutamide) for nmCRPC patients and was the first such FDA-approved treatment for this subset of patients—i.e. those who are no longer responding to ADT but who have no radiological evidence of metastasis. The Erleada (apalutamide) approval followed the release of the results of SPARTAN, a randomized clinical trial of 1,207 patients in which patients received either Erleada (apalutamide) or placebo, discussed at the American Society of Clinical Oncology Genitourinary (ASCO GU) Meeting in February of this year. All of the patients who were enrolled also received hormone therapy. The exciting results showed that the median metastasis-free survival for patients in the Erleada (apalutamide) arm was 40.5 months versus 16.2 months for the placebo group. Both applications received priority review from the FDA due to the exciting results with clear benefit for nmCRPC patients.

The results of another trial known as the PROSPER Trial were also first presented at the 2018 ASCO GU Meeting. In PROSPER, with 1,401 participants, men with nonmetastatic castrate-resistant prostate cancer (nmCRPC) were given either Xtandi (enzalutamide) or placebo; these were men in whom the PSA doubling time was 10 months or less, but, again, there was no evidence of disease seen by CT or bone scan or by MRI. Those nmCRPC patients receiving Xtandi (enzalutamide) had delayed time to metastatic disease or death (whichever occurred first) by a median of 21.9 months, versus placebo (36.6 months compared to 14.7 months), signifying a 71% reduction of the risk for metastasis or death. Another result: Xtandi (enzalutamide) delayed the time until men needed additional cancer treatment, compared to placebo (a median of 39.6 months compared to 17.7 months). On July 13, 2018 the FDA approved Xtandi (enzalutamide) for the treatment of nmCRPC patients.

This means that men with nonmetastatic castrate-resistant prostate cancer now have two choices that they did not have before, when they would simply be continued on ADT. We still do not know, however, if the added Xtandi (enzalutamide) or Erleada (apalutamide) will increase overall survival for these patients.

[This article deals only with nonmetastatic CRPC. There have also been various trials conducted in the metastatic space, and there are other trials currently underway or planned involving anti-androgens such as Zytiga (abiraterone), including some in combinations with other types of therapy, dealing with metastatic disease (mCRPC patients). One of the trials looking at the metastatic disease space is the PEACE1 Trial, which is looking at the benefit of Taxotere (docetaxel) plus ADT, with or without Zytiga (abiraterone) and prednisone, and with or without radiotherapy. This trial is expected to conclude in October 2018 and may help answer the question of whether it is of benefit to patients to add Zytiga (abiraterone acetate) to Taxotere (docetaxel) in metastatic disease that is still castrate-sensitive. The Phase III STAMPEDE Trial showed that adding Zytiga (abiraterone/ prednisone) to standard ADT lowered the relative risk of death by 37% and improved progression-free survival by 71%, versus ADT alone. The CHAARTED Trial looked at Taxotere (docetaxel) plus ADT or ADT alone in patients with metastatic, castrate-sensitive disease, resulting in a greater median survival in the ADT + Taxotere (docetaxel) arm (57.6 months versus 44.0 months with ADT alone).]

Learn more details about these drugs by viewing the Evidence Report from Institute for Clinical and Economic Review (ICER). ICER also held a public hearing on the topic on September 13, 2018 in Chicago.

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