Metastatic Castration-Sensitive Prostate Cancer: the TITAN Study


A key opinion leader reviews how findings from the TITAN study affect treatment of metastatic castration-sensitive prostate cancer.

Bobby Liaw, MD: The TITAN study was an international multicenter, double-blind, placebo-controlled phase 3 clinical trial where they randomized 525 men with metastatic castration-sensitive prostate cancer 1:1 to receive either ADT [androgen deprivation therapy] plus apalutamide or ADT plus placebo. The primary end points of this particular study were radiographic progression-free survival as well as overall survival. Secondary end points included time to cytotoxic chemotherapy, time to pain progression, time to chronic opiate use, and time to skeletal-related events. They also had a couple of exploratory end points, including time to PSA [prostate-specific antigen] progression, second progression-free survival, and time to symptomatic local progression.

I’ll highlight a couple of notable inclusion/exclusion criteria for this study. Patients were allowed to receive previous docetaxel—up to 6 cycles—as part of their metastatic castration-sensitive prostate cancer treatment per the CHAARTED study data that had come out around that time. In fact, about 10.7% of patients had received prior docetaxel on this study. The study also allowed patients with metachronous recurrence of metastatic disease to enroll. This differs a little from some of the studies, such as CHAARTED and LATITUDE, that required patients to be de novo metastatic. In fact, 16.4% of patients on TITAN had undergone prior prostatectomy or radiation therapy for localized disease.

At the time of the first interim analysis, which was shared with us back in 2019, there was a significant improvement in radiographic progression-free survival in patients who received apalutamide. The radiographic progression-free survival at 24 months, at the initial analysis, was 68.2% vs 47.5%, with a very clinically significant hazard ratio of 0.48. We were already seeing a very significant overall survival benefit at 24 months in favor of apalutamide, with a hazard ratio at that point of 0.67.

The final analysis of the TITAN study was shared with us in early 2021. Following unblinding of the arms, patients on the placebo arm were allowed to cross over to receive apalutamide. This ended up being 39.5% of the placebo arm that crossed over. And even with the crossover, in the final analysis, apalutamide retains a significant overall survival advantage, with a hazard ratio of 0.65, reducing risk of death by 35%. The treatment effect on overall survival was favorably consistent across multiple prespecified subgroups. This includes that all-important high-volume vs low-volume disease. We’re seeing a consistent effect across high-volume and low-volume disease.

I’ll also bring up that interestingly, when we look at one of their exploratory end points, apalutamide actually prolonged their secondary progression-free survival significantly. It significantly reduced the risk of death from second progression by 38% when compared with placebo. This isn’t a standard end point, of course. It’s defined as time between initiating the first subsequent therapy and the progression on that first subsequent therapy. But it really goes to reflect and highlight the clinical advantages of early treatment with a drug such as apalutamide off the bat when we’re facing metastatic castration-sensitive prostate cancer.

As part of prespecified exploratory endpoints on the TITAN study, patient-reported outcomes were collected using a variety of different patient surveys, including the Brief Pain Inventory—Short Form, the Brief Fatigue Inventory, the FACT-P [Functional Assessment of Cancer Therapy-Prostate], and the EuroQol Quality of Life 5D questionnaire. Most of these patients came onto the study pretty asymptomatic at baseline.

It’s uplifting to see that patients on the study who experienced pain and fatigue, we’re talking about intensity, it didn’t differ significantly between the groups, between people who got apalutamide and didn’t get apalutamide, and that actually holds for the duration of treatment. The FACT-P survey as well as the EuroQol data showed that there was good preservation of health-related quality of life in both groups. It’s important to highlight that this maintaining of quality of life was despite the addition of an androgen blockade. Taking into context that this is a very active drug that improved survival for patients with metastatic hormone-sensitive prostate cancer, this is a drug that people will end up staying on for a significant amount of time.

When we look at the study, the median treatment duration for someone in the apalutamide arm was something on the order of 39 months. That’s a little more than 3 years. For a drug like apalutamide, which we know can potentially have some adverse effects, to maintain its quality-of-life metrics compared with placebo over the long haul while having a very acceptable safety profile, this demonstrates that we need to heavily consider the use of combination therapy with our men with metastatic hormone-sensitive prostate cancer.

Transcript edited for clarity.

Case: A 73-Year-Old Man With Biochemical Recurrence of Prostate Cancer and Metastatic Castration-sensitive High-volume Disease

January 2018

Initial Presentation

A 73-year-old man presents with urinary retention, fatigue and decreased appetite

Patient History, Lifestyle and Clinical workup

History of mild alcoholic liver cirrhosis

No family history of prostate cancer

Patient is active and is very involved in his grandchildren’s activities

TRUS and biopsy revealed adenocarcinoma of the prostate gland, Gleason score 8 [4+4] with disease in 10/12 cores.

PSA 150 ng/mL; Hb 9.7 g/dL; ANC 1.9

Liver function tests are abnormal

Initial Diagnosis and Treatment

Patient is diagnosed with localized prostate cancer

He undergoes robotic radical prostatectomy with subsequent PSA decrease (12 ng/mL)

CT and bone scans showed no residual disease

October 2019

Presentation at Recurrence

Patient complains of right hip pain and abdominal pain

Imaging with CT and bone scan showed multiple metastatic bone lesions in the pelvis and diffuse liver lesions

PSA 90 ng/mL; Hb 9.4 g/dL; ANC 1.5

Liver function tests continue to be abnormal

Diagnosis of Recurrence

Patient is diagnosed with biochemical recurrence of prostate cancer with high-volume castration-sensitive metastatic disease

Germline genetic testing is negative

Treatment for Recurrence

Patient wishes to receive oral treatment with good quality of life so he can continue to be involved in his grandchildren’s activities

Due to his abnormal liver function tests and desire to receive oral treatment, he is started on ADT + apalutamide

At his 1-year follow-up, the patient’s PSA remains undetectable

Follow-up imaging shows stable disease, and he continues to report a good quality of life

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