Apalutamide Maintains Health-Related Quality of Life in TITAN Trial

Neeraj Agarwal, MD

Neeraj Agarwal, MD

The addition of apalutamide (Erleada) to androgen deprivation treatment (ADT) improved time to pain progression and other quality-of-life out­come measures in patients with metastatic castration-sensitive prostate cancer (mCSPC) in the phase III TITAN trial. These results demonstrate that the regimen preserves health-related quality of life (HRQOL) in thisvpatient population, according to Neeraj Agarwal, MD, who presented the data at the 11th European Multidisci­plinary Congress on Urological Cancers.¹

“In addition to substantial benefit in dual TITAN pri­mary end points of overall survival and radiographic progression-free survival, the overall health-related quality of life was preserved with apalutamide, including patients with high-volume or low-volume of disease, prior docetaxel use, or prior treatment for localized disease,” Agarwal, associate professor of medicine at the Univer­sity of Utah and director of the Genitourinary Oncology Program at Huntsman Cancer Institute, both in Salt Lake City, Utah, said during a presentation of the data.

Previously reported data from the study have already confirmed benefits with apalutamide versus placebo plus ADT in the described patient population.²The dual primary end points of overall survival (OS) and radio­graphic progression-free survival (rPFS) were previous­ly reported and led to the approval of apalutamide for this patient population in 2019.³

The TITAN clinical trial results, published in theNew England Journal of Medicinein July 2019, showed the rPFS rate at 24 months was 68.2% for apalutamide and 47.5% for placebo (HR, 0.48; 95% CI, 0.39-0.60;P<.0001).²The OS rate was 82.4% at 24 months in the apalutamide group and 73.5% in the placebo group (HR, 0.67; 95% CI, 0.51-0.89;P= .005), translating to a 33% lower risk of death in the experimental group.²

Secondary end points included time to pain progression, which was evaluated using the Brief Pain Inventory-Short Form (BPI-SF) where pain scores range from 0 through 10. Other secondary end points included time to initiation of cytotoxic chemotherapy, time to chronic opioid use, and time to skeletal-related event.²If median values for end points were not reached, 25th percentiles were used.

In the study results presented at the meeting, patient-reported outcomes for efficacy and adverse effects (AEs) were evaluated using questionnaires. These included the BPI-SF, Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EuroQoL Group EQ-5D-5L questionnaire. BPI-SF and BFI were completed for 7 consecutive days (day —6 through day 1 of each cycle visit), then at 4, 8, and 12 months during follow-up. FACT-P and EQ-5D-5L were completed at cycle 1 through cycle 7, then at every other cycle through the end of treatment, and at 4, 8, and 12 months during follow-up.

Time to pain progression consistently favored the apalutamide group versus the placebo group (TABLE).¹Patients who had the most severe pain at baseline saw the most improvements. The median pain scores were 1.14 for the apalutamide group and 1.00 for the placebo group.

&ldquo;Pain, in my view, is a reflection of efficacy. Not surprisingly, pain scores were much better with [the] apalutamide arm, whether it was pain progression, pain intensity, pain interference, or average pain,&rdquo; Agarwal said.

Quality of life and fatigue were the most crit&shy;ical outcomes that were evaluated based on the questionnaires. The addition of apalutamide to ADT in these patients did not increase fatigue intensity or fatigue interference. The median fatigue-intensity scores at baseline were 1.29 for the apalutamide group and 1.43 for the placebo group, with the median time to fatigue intensity not reached in either group and 25th percentiles of 9.2 months and 11.0 months, respectively (HR, 1.09; 95% CI, 0.88-1.35;P= .4428). Similarly, fatigue interference was not affected by the addition of apalutamide, with a 25th percentile of 10.2 months versus 10.5 months with placebo (HR, 1.01; 95% CI, 0.81-1.26;P= .9256).

Based on the FACT-P total score and the EQ-5D-5L data, HRQOL was preserved with the addition of apalutamide to ADT. Median time to deterioration in FACT-P total score was 8.9 months and 9.2 months with apalutamide and placebo, respectively (HR, 1.0; 95% CI, 0.9-1.2;P= .854).

Rash was observed to be a common AE with apalutamide treatment, and the extent to which treatment-associated rash interfered with QOL was assessed using theside-effect botherquestion in the FACT-P questionnaire. The apalutamide and placebo arms showed similar tolerability for rash based on the FACT-P score.

The TITAN trial is a double-blind phase III trial that enrolled 1052 patients with mCSPC who were randomized 1:1 to the apalutamide (n = 525) or placebo groups (n = 527). All patients had a background of ADT and at least 1 lesion on bone scan, indicating distant metastasis. Patients who could have received ADT up to 6 months prior to randomization were selected and stratified by Gleason score (&le;7 vs &ge;8), geographical region of enrollment (European Union and North America vs other countries), and prior docetaxel treatment (yes vs no). Of those patients, 16.4% had undergone prostatectomy or received radiotherapy for localized disease; 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease; and 37.3% had low-volume disease. The study was conducted across 260 sites in 23 countries.

References

1. Agarwal N, Mcquarrie K, Bjartell A et al. Patient-reported outcomes (PROs) from TITAN: A phase 3, randomized, double-blind study of apalut&shy;amide (APA) versus placebo (PBO) added to androgen deprivation therapy (ADT) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC).Ann Oncol. 2019;30(suppl 5):330-331.
2. Chi KN, Agarwal N, Bjartell A et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer.N Engl J Med. 2019;381(1):13-24. doi: 10.1056/NEJMoa1903307.
3. FDA approves apalutamide for metastatic castration-sensitive prostate cancer. FDA website. bit.ly/2O39Y3z. Published September 17, 2019. Accessed January 27, 2020.