Choosing AR-Targeted Therapy in CSPC

Part 2: Updated Results Show Long-Term Survival Benefit for Apalutamide in mCSPC

During a live virtual event, Matthew B. Rettig, MD, discussed the results of the TITAN trial of apalutamide for patients with metastatic castration-sensitive prostate cancer.

Targeted OncologyTM: Please describe the design and goals of the TITAN trial (NCT02489318).

RETTIG: This was the phase 3 randomized controlled trial that led to the regulatory approval of apalutamide [Erleada] for this metastatic castration-sensitive prostate cancer [mCSPC] patient population.1 The population included patients who had de novo or recurrent mCSPC. The patients had to have good performance status, and they were required to be on androgen deprivation therapy [ADT] continuously. They were allowed to have previously received docetaxel, and about 10% to 11% of the patients had received docetaxel.2 They had to be on ADT for less than 6 months if it was started from metastatic disease, or less than 3 years for local disease, and the treatment had to be completed for 1 year prior in that case.

The patients were stratified per Gleason score, geographic region, and prior chemotherapy. It was a 1:1 randomization between December 2015 to July 2017 to apalutamide at the standard dose of 240 mg versus placebo, and there were coprimary end points of overall survival [OS] and radiographic progression-free survival [rPFS]. There were several secondary end points and some exploratory end points, including an interesting exploratory end point called PFS2, second progression-free survival.

Could you describe the patient population of this trial?

The patients were well balanced. As we see in almost all of these studies, about 60% to two-thirds of the patients who enrolled in these trials have high-volume disease. Most of the patients had M1 disease at diagnosis. So, that means they had de novo mCSPC, whereas the M0 patients have recurrent mCSPC.

Most of them had appropriate performance status and a Gleason score of 7 or higher. If they had a Gleason score less than 7, that was an error. There is no such thing as a Gleason score 6 tumor that metastasizes; that’s probably either a miscategorization, or the patient only had a prostate needle biopsy and did not have a radical prostatectomy, which will upgrade those Gleason score 6s in about 30% of the cases. Only about 10% to 11% of the patients had prior chemotherapy, and their baseline pain is fairly mild in this population—which also has a good performance status.

What was the OS observed in this trial?

We have OS data from the final analysis after 44 months.3 This is from the Journal of Clinical Oncology, while I believe the original New England Journal of Medicine article presented data at 29 months.2 The data held up. The hazard ratio was almost identical here as it was in in the original article, and that’s a hazard ratio of 0.65 [95% CI, 0.53-0.79; P = .0001].3 The placebo arm reached about 4.5 years [before crossing below 50% OS rate.

The investigators did an analysis where they accounted for crossover from placebo to apalutamide, and if you exclude those patients who crossed over, the magnitude of the benefit is even higher. It’s an artificial way of looking at it, but that is the case.

In addition to OS, it also markedly improved rPFS, time to prostate-specific antigen progression, time to castration resistance, and time to initiation of chemotherapy.2,4 In health-related quality-of-life [QOL] questionnaires that were administered during the study, the study staff were not allowed to help the patients. So, they’re completed only by the patient, and it’s the patient reporting their true sense of their QOL. There was no difference in QOL.3

What stood out about the subgroups in the TITAN trial?

There were about 110 patients with prior docetaxel use, and there’s clearly no benefit there in the docetaxel. There are too few patients, but given the data with ENZAMET [NCT02446405], with enzalutamide [Xtandi] where half of the patients had prior docetaxel and there was no benefit,5 I would be suspect of saying that apalutamide added to docetaxel would benefit. It’s probably because of a drug interaction where apalutamide induces or activates CYP3A4, which metabolizes docetaxel, probably rendering docetaxel levels lower. So overall, apalutamide is pretty easy to use, and it benefited patients with low- and high-volume disease.3

How did apalutamide perform in terms of the trial’s secondary end points?

Time to chemotherapy was improved, but median time to pain progression was not; it did not reach statistical significance.2,4 The secondary end points were tested in a hierarchical fashion, so that once you get to pain progression, if it doesn’t reach a statistical significance, investigators don’t perform a statistical P value for the subsequent secondary end points of chronic opioid use and time to skeletal-related event.

What were the patient-reported outcomes in this trial?

The curves [for the apalutamide and placebo arms] for patient-reported outcomes overlap throughout the course.3 If anything, the apalutamide may be a little bit higher at the very end. But there’s certainly no decrement in the QOL based upon patient-reported outcomes. And I think that’s important to emphasize when telling patients. I certainly tell them that if you take apalutamide, you’re not going to feel any difference in your QOL versus if you didn’t take it.


1. FDA approves apalutamide for metastatic castration-sensitive prostate cancer. FDA. Published September 17, 2019. Accessed March 17, 2022.

2. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307

3. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: Final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488

4. Chi KN, Agarwal N, Bjartell A, et al. First results from TITAN: A phase III double-blind, randomized study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT). J Clin Oncol. 2019;37(15)suppl.:5006:5006. doi: 10.1200/JCO.2019.37.15_suppl.5006

5. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835