Jorge Garcia, MD, and Kim Chi, MD, share their insights on the LATITUDE trial in prostate cancer.
Jorge A. Garcia, MD
Adding abiraterone acetate (Zytiga) plus prednisone to androgen deprivation therapy (ADT) lowered the risk of death by 38% in men with newly diagnosed, high-risk, metastatic prostate cancer, according to findings from the phase III LATITUDE trial presented at the 2017 ASCO Annual Meeting.
After a median follow-up of 30.4 months, the median overall survival (OS) had not yet been reached in the abiraterone cohort and was 34.7 months with ADT alone (HR, 0.62; 95% CI, 0.51-0.76; P <.0001). The 3-year OS rates were 66% with abiraterone versus 49% in the control arm. Median PFS was 33 months versus 14.8 months, respectively (HR, 0.47; 95% CI, 0.39-0.55; P <.0001).
During the ASCO meeting, OncLive discussed these practice-changing findings with Jorge Garcia, MD, Department of Hematology and Oncology, Cleveland Clinic, and Kim Chi, MD, associate director of clinical research, Vancouver Prostate Centre.Garcia: The standard of care for many years for men with prostate cancer has been castration, oftentimes orchiectomy or we do ADT therapy, which is basically hormonal suppression. That treatment protocol changed a couple years ago with the results of CHAARTED and also with STAMPEDE, where we demonstrated that adding docetaxel to ADT lead to survival improvement in men with castration-sensitive metastatic disease.
So, since a couple years ago, the standard for us has been ADT and chemotherapy. Now, the caveat with that data is the benefit that we have seen with adding chemotherapy appears to be derived only for patients with high-volume metastases. For high-volume metastases, the intergroup data in America has been somewhat arbitrary but has been used for many years. Which is, men with visceral disease, men who have more than 3 bone lesions, 1 of which has to be outside of the pelvis or spine, and a Gleason score of 8 or greater.
LATITUDE, as well as the second arm from STAMPEDE, looked at the addition of abiraterone acetate to the backbone of ADT, which is what we reviewed at ASCO. Around 1000 castration-sensitive patients were randomized to either ADT plus placebo, or ADT plus oral therapy with abiraterone and prednisone. The primary endpoint was survival, and the hazard ratio for that was actually 0.62, an almost 38% risk reduction in mortality if you get abiraterone upfront with ADT.
In LATITUDE, we looked at 2 out of those 3 risk factors for inclusion for the definition of high-volume disease, which is, again, different than what we saw for CHAARTED. So, if we look at the makeup of patients with a Gleason score of 8 or higher in CHAARTED, it’s roughly the same number of patients that we have seen in LATITUDE. So, to us, the patient population is basically the same—there isn’t much difference in the makeup of those patients.
I think the important part is, adding abiraterone upfront not only makes people live longer, but also reduces the risk of relapse by more than double, 14 months for ADT alone versus 33 months with ADT and abiraterone. The addition of abiraterone delayed progression, skeletal-related events, PSA declines, and time to chemotherapy, as well, so it is a pretty powerful trial. Chi: What surprised me in the analysis when I first saw it several months ago was the degree of benefit. I do not think any of us were expecting this. Since it was a high-risk or poor prognosis patient population, the degree of benefit was a good surprise. Additionally, the secondary endpoints were also in favor of the combination therapy.
This was a first interim analysis, which makes it more remarkable, because the study was very positive, showing an overall survival advantage for patients who received androgen deprivation therapy with abiraterone and prednisone. The hazard ratio was 0.62, meaning there was a 38% reduction in the risk of death. The P value was less than .0001, showing that this study is very positive and, therefore, all the other patients who were on placebo were crossed over. Not only was this the first interim analysis, it is also now the final analysis.
All of the patients have been crossed over, so they will continue to be followed up, but we won’t expect any further data. We will be reporting on health-related quality of life and patient-reported outcomes, and we’ve submitted some data to the ESMO meetings which we will hear about in SeptemberGarcia: I think that these data will certainly change how we practice now. The biggest questions right now as a clinician are, “How do I pick my patient? Who gets chemo, and who gets ADT and abiraterone?” We don’t have any head-to-head data, so we simplistically looked at those 2 trials and tried to make the best of what we do have, but I think most patients will be excited to get an oral agent instead of systemic chemotherapy.
The challenge is, chemo is usually given for 6 cycles over 4 to 5 months, whereas oral therapy requires about 3 years, if you look at the median PFS in that trial. That means that you have to start a patient with 3 years’ worth of abiraterone and prednisone, which is costly. So, we have to start dissecting if it is more cost-effective to do chemotherapy upfront or to put people on oral therapy for 3 years. Chi: We have to look at the pros and cons of the treatment. Previously, when we were using chemotherapy in combination with androgen deprivation therapy for patients, we tended to shy away from treating lower-risk patients because of the toxicity of chemotherapy. Now that we have a much less toxic therapy with abiraterone, there may be more incentive to treat all patients who are starting on androgen deprivation therapy with a combination with abiraterone. We also must weigh the risks of long-term treatment with abiraterone plus prednisone and the toxicity over those 2 years that patients are going to be on therapy, as well as the financial toxicity of having to treat patients.
These questions will arise, as well as how we decide to apply this treatment to our patient populations. For the patient with a high-volume or high-risk metastatic prostate cancer, I think they should get this treatment. I think we should be able to start using abiraterone with androgen deprivation therapy instead of chemotherapy.
In terms of combining androgen deprivation therapy with chemotherapy and abiraterone, that is an unanswered question. There are some trials that have just completed accrual investigating this modality. There is TITAN which is looking at apalutamide (ARN-509) with androgen deprivation therapy versus androgen deprivation therapy alone, but it allows the use of docetaxel chemotherapy.
The ENZAMET trial has also just recently completed accrual and is investigating androgen deprivation therapy with or without enzalutamide (Xtandi). Docetaxel was allowed in that trial, as well. By looking at some of those subgroup analyses, we’ll get an idea about whether combining all 3 therapies is more beneficial.Garcia: Well, ADT alone becomes an obsolete treatment. I think the biggest question before LATITUDE was low-volume patients—patients who didn’t meet the CHAARTED definition for high-volume. When you look at STAMPEDE, which included low-volume patients, and then you look at LATITUDE, most of us would now argue that regardless of volume of disease, when they present with metastatic disease, they should get an oral therapy.
Chi: We’ve had abiraterone in our armamentarium for many years now for metastatic castration-resistant prostate cancer, so most people are quite familiar with the side effects—which are related to increased mineralocorticoids—including hypokalemia, hypertension, fluid retention, and elevated liver enzyme tests. These occurred in about 5% of patients in terms of a grade 3 or 4 toxicity, making it important to watch out for them.
Fizazi K, Tran N, Fein LE, et al. LATITUDE: A phase III, double-blind, randomized trial of androgen deprivation therapy with abiraterone acetate plus prednisone or placebos in newly diagnosed high-risk metastatic hormone-naive prostate cancer. J Clin Oncol 35, 2017 (suppl; abstr LBA3).