Neeraj Agarwal, MD, discusses the TITAN trial and the implications in prostate cancer treatment.
Neeraj Agarwal, MD
Beyond the positive overall survival (OS) and radiographic progression-free survival (rPFS) data with apalutamide (Erleada) plus androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer, the androgen receptor (AR) inhibitor also maintains health-related quality of life (HRQoL), said Neeraj Agarwal, MD.
In the phase III TITAN trial, results showed that apalutamide plus ADT led to a 33% reduction in the risk of death compared with placebo/ADT in this patient population (HR, 0.67; 95% CI, 0.51-0.89;  P  = .0053).1 Based on these data, the FDA approved apalutamide in September 2019 for the treatment of patients with metastatic castration-sensitive prostate cancer.
Moreover, health-related quality of life was preserved with the addition of apalutamide, and pain and fatigue were improved, according to updated data presented at the 2019 ESMO Congress.2 For the majority of patients in both arms, pain and fatigue remained stable or improved during treatment, with greater improvements observed in patients who had higher baseline severity scores. Functional Assessment of Cancer Therapy-Prostate total score and Euro QoL Group EQ-5D-5L data demonstrated had a similar maintenance of overall HRQoL in both arms.
"Most remarkably, the fatigue, which is synonymous with these AR inhibitors was not worse," explained Agarwal. "In fact, patient experienced similar level of fatigue in both arms. From these data, I [conclude] that apalutamide is improving survival in a very significant fashion for OS and rPFS, and delaying pain. At the same time, it is preserving the HRQoL and not making fatigue worse. This is great news for our patients."
Though next steps are not planned yet, Agarwal believes identifying relevant biomarkers will be crucial.
"Going forward, biomarkers will be the key," said Agarwal. "Selecting patients based on underlying biomarkers and predicting response, or lack of response, so that we can minimize adverse events and improve survival and quality of life."
In an interview with  OncLive  during the 2019 ESMO Congress, Agarwal, associate professor of medicine, University of Utah School of Medicine; and director, Genitourinary Oncology Program, Oncology Division, co-leader, Urologic Oncology Multidisciplinary Program, associate director of Clinical Trials, Huntsman Cancer Institute, discussed the TITAN trial and the implications in prostate cancer treatment.
OncLive:  Could you outline the design of the TITAN trial and the initial findings?
Agarwal:  The  TITAN trial was a large, phase III randomized trial, which recruited more than 1000 patients with newly diagnosed metastatic castration-sensitive prostate cancer, and randomized them to receive standard-of-care ADT versus ADT with apalutamide, which is a potent, novel AR inhibitor.
There were dual primary endpoints of rPFS and OS. The study found that apalutamide plus ADT was superior to ADT alone for both endpoints. There was a 52% reduction in the risk of radiographic disease progression, and there was a very impressive improvement in OS with a 37% reduction in the risk of death. These data are very impressive, and not surprisingly, they led to approval of apalutamide for patients with metastatic castration-sensitive prostate cancer.
HRQoL was assessed very rigorously using multiple standard skills, such as FACT-P and Euro QoL Group EQ-5D-5L Scores, which included brief pain, grief, and fatigue inventories. This assessment was performed at every cycle when patients were coming for the treatment starting 7 days before until 1 day after the cycle.
Even after patients progressed on their respective treatments, they continued to have these quality-of-life (QoL) measurements obtained periodically. Therefore, these patients were undergoing very rigorous assessment as far as how they were feeling on treatment. We found that the HRQoL was preserved despite the deeper androgen blockade induced by apalutamide. These patients were surviving longer and their QoL was preserved.
Could you elaborate on the implications of these findings?
When patients come to us seeking treatment for newly diagnosed metastatic castration-sensitive prostate cancer, obviously living longer is one of the major objectives. At the same time, living longer with good QoL is an even bigger objective. From that perspective, these data are very encouraging and I'm going to share it with my patients for sure.
Following these data, what are the next steps?
What we do now that we have improved survival, improved rPFS, and OS? We realize that we have not cured these patients. They are eventually going to progress even after receiving treatment with apalutamide. That is challenging for these patients to face and treatment options are limited. [The other options] consist of mostly chemotherapy drugs and others with a modest OS benefit in the range of 3 months.
The challenge is to find newer treatment options. We have been working on various novel therapeutic options including immunotherapy. If I bet on one class of drugs, it would immunotherapy. It could be immune checkpoint inhibitors, but second-generation, third-generation immunotherapeutic options. That class of drugs is known to improve survival without impacting QoL in a significant fashion.
There are other emerging classes of drugs. At the 2019 ESMO Congress, we saw data on olaparib (Lynparza) for patients who have DNA repair defects in their tumors. This was the first positive trial selecting patients based on a biomarker. It's a very positive step in the right direction.
What other agents are being explored in this field?
There are many checkpoint inhibitors, such as pembrolizumab (Keytruda), atezolizumab (Tecentriq), and nivolumab (Opdivo) being tested in the setting of metastatic castration-resistant prostate cancer. Many of those drugs have been or are being combined with docetaxel, with PARP inhibitors, such as olaparib, or traditional AR inhibitors, such as enzalutamide (Xtandi). Time will tell how these data are going to pan out in large clinical trials.