Preeti Ramadoss, PhD

The addition of apalutamide (Erleada) to androgen deprivation treatment (ADT) improved time to pain progression and other quality-of-life out&shy;come 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 Multidisci&shy;plinary Congress on Urological Cancers.

&ldquo;In addition to substantial benefit in dual TITAN pri&shy;mary 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,&rdquo; Agarwal, associate professor of medicine at the Univer&shy;sity 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.

The dual primary end points of overall survival (OS) and radio&shy;graphic progression-free survival (rPFS) were previous&shy;ly reported and led to the approval of apalutamide for this patient population in 2019.

The TITAN clinical trial results, published in the

in 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;

The 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;

= .005), translating to a 33% lower risk of death in the experimental group.

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.

If 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 (

Patients 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;

= .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;

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;

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 the

question 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.

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).

Chi KN, Agarwal N, Bjartell A et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer.

. 2019;381(1):13-24. doi: 10.1056/NEJMoa1903307.

FDA approves apalutamide for metastatic castration-sensitive prostate cancer. FDA website. bit.ly/2O39Y3z. Published September 17, 2019. Accessed January 27, 2020.

Articles

The addition of apalutamide to androgen deprivation treatment improved time to pain progression and other quality-of-life out&shy;come measures in patients with metastatic castration-sensitive prostate cancer in the phase III TITAN trial.

Apalutamide Maintains Health-Related Quality of Life in TITAN Trial

Patients with advanced or metastatic urothelial cancer harboring

alterations who had progressed on or were intolerant to plat&shy;inum-based chemotherapy saw promising responses with infigratinib monotherapy, with marked improve&shy;ments seen in upper tract urothelial carcinoma (UTUC) specifically. Frequencies of certain genomic mutations associated with UTUC versus urothelial carcinoma of the bladder (UCB) may serve as the rationale for differ&shy;ing response rates, Sumati V. Gupta, MD, said during a presentation of the data at the 11th European Multidis&shy;ciplinary Congress on Urological Cancers.

Data for the analysis came from an expansion cohort of a phase I study of infigratinib in patients with advanced or metastatic urothelial carcinoma with

-activating mutations or fusions and prior plati&shy;num-based chemotherapy, unless contraindicated.

The study enrolled 67 patients, 8 of whom had UTUC. Seventy percent of these patients had received &ge;2 prior antineoplastic therapies. Patients received daily oral infigratinib 125 mg for 3 weeks on and 1 week off. The overall response rate was 25.4%, and the disease control rate (DCR) was 64.2%.

In the overall cohort, the most common adverse effects observed were hyperphosphatemia, elevated creatinine, fatigue, constipation, and decreased appetite.

In the current analysis, investigators examined the difference in response rate to infigratinib treatment between patients with UCB and UTUC. Of the 8 patients with UTUC, 1 had a complete response (CR) and 3 had a partial response. The remaining patients with UTUC had a best response of stable disease, for a DCR of 100%. One patient with UTUC and a tumor bearing an

fusion responded to treatment with infi&shy;gratinib and had CR at day 55, which continued until disease progression at day 260.

Patients with UTUC also achieved longer median progression-free survival (8.54 versus 3.65 months) and overall survival (21.8 versus 7.0 months) com&shy;pared with patients with UCB.

Genomic profiling used DNA isolated from forma&shy;lin-fixed, paraffin-embedded tumor tissue samples and cell-free DNA (cfDNA) obtained from plasma from study patients. DNA from tissue samples from 39 UCB and 7 UTUC tumors were analyzed, and oncoplots were generated. Alterations were seen in

per the study criteria; genomic alterations to the

by deletions or mutations, chromatin-remodeling gene alterations, and activation of

were commonly co-occurring in UCB and UTUC samples. The frequencies of alterations varied in UCB versus UTUC, which are comparable to results of a prior study demonstrating differences in frequencies in gene alterations between these cancer types.

The oncoplots demonstrate a more complex genom&shy;ic profile, with an increased number of known or likely deleterious mutations and copy number alterations in tissue from patients with urothelial carcinoma of the bladder versus [patients with] upper tract urothelial carcinoma,&rdquo; said Gupta, who is an assistant professor in the Division of Oncology, Department of Medicine, at University of Utah&rsquo;s Huntsman Cancer Institute in Salt Lake City. &ldquo;Amplification of genes involved in

ligands FGF3, -5, and -19 on chromosome 11 and

, were more common in UCB compared with UTUC.&rdquo;

promoter mutations were seen in both groups; however, they were more common in patients with UCB. Only 1 patient with UTUC had a significantly high muta&shy;tional load, but this was likely due to a mutation in

which is involved in DNA mismatch repair. Mutations in regions outside the immunoglobulin-like domain were seen in UCB samples only. Additionally,

R248RC mutations were more com&shy;mon and

S249C mutations were less common in UTUC versus UCB.

alterations in cfDNA were concordant with the alterations seen in tissue samples in 79% of patients for whom both tumor tissue samples and cfDNA were available (39 patients with UCB and 5 with UTUC). &ldquo;Again, a more complex genomic profile was seen with an increased mutational load in patients with bladder cancer versus patients with upper tract urothelial carci&shy;noma,&rdquo; Gupta said.

The investigators attempted to correlate clinical char&shy;acteristics of the disease to the presence or absence of

mutations in cfDNA for samples with at least 1 genetic alteration detected in the plasma. These characteristics included tumor length, ECOG performance status, and sites of metastases. However, the inves&shy;tigators found no correlation between

allele frequency and clinical characteristics with response. A previous study suggested that the differences in genetic alteration frequencies may be important when considering targeted therapies for UCB versus UTUC.

&ldquo;We concluded that different patterns of genomic alterations are seen in patients with urothelial cancer of the bladder and upper tract urothelial carcinoma,&rdquo; Gupta said. &ldquo;This underscores the distinct biology of these diseases.&rdquo;

Gupta concluded by stating that the results with infi&shy;gratinib in UTUC support a planned phase III adjuvant study, predominantly in this population. The planned study, PROOF 302 (NCT04197986), is comparing adju&shy;vant infigratinib versus placebo for invasive urothelial carcinoma with susceptible

De Giorgi U, Pal SK , Rosenberg JE, et al. Activity of the FGFR13 inhibitor infigratinib in patients with upper tract urothelial carcinoma and urothelial carcinoma of the bladder: latest efficacy findings and comprehensive genomic profiling/cell-free DNA data.

. 2019;18(11):e3405-e3406. doi: 10.1016/S1569-9056(19)34582-8.

Pal SK, Rosenberg JE, Hoffman-Censits JH, et al. Efficacy of BGJ398, a fibroblast growth factor receptor 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with

. 2018;8(7):812-821. doi: 10.1158/2159-8290.CD-18-0229.

Sfakianos JP, Cha EK, Iyer G, et al. Genomic characterization of upper tract urothelial carcinoma.

. 2015;68(6):970-977. doi: 10.1016/j.eururo.2015.07.039.

Frequencies of certain genomic mutations associated with upper tract urothelial carcinoma versus urothelial carcinoma of the bladder may serve as the rationale for differ&shy;ing response rates, Sumati V. Gupta, MD, said during a presentation of the data at the 11th European Multidis&shy;ciplinary Congress on Urological Cancers.

Preeti Ramadoss, PhD | Authors

Articles

Apalutamide Maintains Health-Related Quality of Life in TITAN Trial

Infigratinib Treatment Induces Responses in Urothelial Carcinoma, Leading to Phase III Trial