Jason Broderick

Intensification of androgen-deprivation therapy (ADT) in addition to apalutamide (Erleada) elicited promising efficacy as a treatment for patients with high-risk biochemically relapsed prostate cancer, according to findings from the phase 3 PRESTO trial presented at the 2022 ESMO Congress.

The findings also showed, however, that the further addition of abiraterone acetate (Zytiga) and prednisone to the apalutamide/ADT regimen did not significantly boost clinical outcomes.

At a median follow-up of 21.5 months, the median PSA progression-free survival (PSA PFS) was 24.9 months (95% CI, 23.3-32.3) with apalutamide plus ADT versus 20.3 months (95% CI, 18.2-22.9) with ADT alone (HR, 0.52; 95% CI, 0.35-0.77; 

At a median follow-up of 21.3 months, the median PSA PFS was 26.0 months (95% CI, 22.9-32.5) with ADT + apalutamide + abiraterone/prednisone versus 20.0 months (95% CI, 18.2-22.5) with ADT alone (HR, 0.48; 95% CI, 0.32-0.71; 

“The addition of apalutamide to ADT for a finite duration of treatment leads to a statistically significant prolongation of PSA PFS without an adverse impact on time to testosterone recovery,” said lead author Rahul Aggarwal, MD, associate professor of Hematology/Oncology, University of California, San Francisco (UCSF), and associate director for Clinical Sciences, UCSF Helen Diller Family Comprehensive Cancer Center.

“Though not powered to compare experimental arms, there does not appear to be a substantial additional clinical benefit with the addition of abiraterone and prednisone to apalutamide, and there was increased toxicity in this arm,” added Aggarwal.

Inclusion criteria for the open-label PRESTO study (NCT03009981) were prior radical prostatectomy with subsequent biochemical recurrence (PSA >.05 ng/mL) and a PSA doubling time (PSA-DT) ≤9 months. Patients could not have metastases found on conventional imaging, including a CT and bone scan, and must have received prior adjuvant/salvage radiation unless not eligible for radiotherapy. Prior ADT was allowed, as long as the last dose was >9 months prior to study enrollment.

There were 503 patients randomized in a 1:1:1 ratio to receive ADT monotherapy (LHRH analog; Arm A; 166 patients); ADT (LHRH analog) plus apalutamide (Arm B; 168 patients); or ADT + apalutamide + abiraterone + prednisone (Arm C; 169 patients).

“In all 3 arms, patients were treated for a finite duration of 52 weeks in the absence of PSA progression or unacceptable toxicity,” said Aggarwal. “Following treatment completion, patients were followed with mostly lab assessment until PSA progression, at which point, treatment was per investigator discretion.”

The primary end point of the study was to compare each experimental arm (B and C) to the control arm of ADT alone (Arm A) with respect to PSA PFS. “PSA progression was defined as an increase in PSA of nadir + 2 ng/mL during treatment or >0.2 ng/mL following treatment confirmed by repeat measurement,” explained Aggarwal.

Key secondary outcome measures were PSA PFS in the testosterone-evaluable population (subgroup that achieved a serum testosterone level >50 ng/dL following treatment completion), medium time to testosterone recovery (a level >50 ng/dL), and safety.

Aggarwal said patient and disease characteristics at baseline were well balanced among the 3 study arms. Across the overall study population, the median age was 66.7 years (range, 61.2-70.9). The majority of patients on the trial were either White (83.7%), Black or African-American (6.4%), or Asian (2.6%). Regarding ethnicity, 91.1% of patients were non-Hispanic, 5.4% were Hispanic, and 3.6% were “unknown/not reported/missing.”

“It is worth noting that although the investigational sites were broadly geographically distributed across the United States, the enrollment of Black and Hispanic men fell short of US population percentages,” said Aggarwal.

The median PSA at baseline was 1.77 ng/mL. The PSA DT was <3 months for 25.8% of patients and between 3 and 9 months for 74.2% of patients. The median time between radical prostatectomy and baseline was 4.4 years. Overall, 84.7% of patients had prior radiation and 42.35% of patients had prior ADT.

A preplanned subgroup analysis based on stratification by PSA DT showed a consistent benefit with both experimental arms versus the control arm, regardless of the length of PSA DT. In the comparison of apalutamide plus ADT vs ADT alone, the HR for PSA PFS was 0.57 in patients with a PSA DT <3 months and 0.50 in patients with a PSA DT of between 3 and 9 months. Comparing ADT + apalutamide + abiraterone/prednisone vs ADT alone, the HR for PSA PFS was 0.46 and 0.48 in the <3 months and 3-to-9 months PSA DT subgroups, respectively.

Similarly, when assessing PSA PFS in patients with testosterone recovery (testosterone evaluable population), the HR for PSA PFS showed a benefit in both the ADT plus apalutamide arm (HR, 0.53; 

 = .00197) and the ADT + apalutamide + abiraterone/prednisone arm (HR, 0.60; 

 = .00851) versus the ADT alone arm that was comparable to the benefit observed in the overall study population.

Aggarwal also noted that, “The addition of apalutamide to ADT did not adversely impact the time to testosterone recovery following treatment completion. With the further addition of abiraterone, we saw a slight prolongation in time to testosterone recovery, though this did not reach statistical significance.”

Regarding safety, Aggarwal explained that the incidence of grade 3/4 and serious adverse events (AEs) was increased with the addition of abiraterone in Arm C. Across the study arms, grade 3/4 AEs occurred in 18.8%, 25.2%, and 37.9% of Arms A, B, and C, respectively, and serious AEs occurred in 8.1%, 8.6%, and 17.4% of the 3 arms, respectively.

While adding apalutamide to ADT did not appear to lead to an increase in the most commonly observed grade ≥2 AEs, the addition of abiraterone in Arm C increased the incidence of grade ≥2 hypertension (30.4%) versus Arm B (22.7%) and Arm A (19.4%).

“Follow-up is ongoing to estimate the impact of ADT plus AR pathway inhibition on patient-reported outcomes, time to castration resistance, and metastasis-free survival,” Aggarwal said in his concluding remarks.

“Given that treatment decisions in biochemically recurrent prostate cancer are often predicated on PSA kinetics alone, ADT plus apalutamide for a fine treatment period could be considered for select high-risk patients with a short PSA doubling time,” he added.

1. Aggarwal R, Heller G, Hillman D, et al. PRESTO: A phase III, open-label study of androgen annihilation in patients (pts) with high-risk biochemically relapsed prostate cancer (AFT-19).

. 2022;33(suppl 7):S808-S869. doi: 10.1016/annonc/annonc1089

Articles

Androgen-deprivation therapy with the addition of apalutamide was effective when used in patients with high-risk biochemically relapsed prostate cancer.



Apalutamide Plus ADT Shows Promise in High-Risk Biochemically Relapsed Prostate Cancer

Adjuvant atezolizumab (Tecentriq), given post-resection, did not improve clinical outcomes vs placebo in patients with renal cell carcinoma (RCC) at increased risk of recurrence, according to findings from the phase 3 IMmotion010 trial presented at the 2022 ESMO Congress.

At a median follow-up of 44.7 months (IQR, 39.1-51.0), the median investigator-assessed disease-free survival (DFS) was 57.2 months (95% CI, 44.6 – not evaluable) with atezolizumab compared to 49.5 months (47.4 – not evaluable) with placebo (HR, 0.93; 95% CI, 0.75-1.15; 

 = 0.50). The 2-year DFS rates were 67% vs 65%, respectively.

“There was no evidence that atezolizumab reduced the risk of recurrence versus placebo,” said first author Axel Bex, MD, PhD, Royal Free London NHS Foundation Trust and UCL Division of Surgery and Interventional Science, Netherlands/UK, adding that there was also “no evidence of reduction in the risk of death with atezolizumab.”

The double-blind phase 3 IMmotion010 trial (NCT03024996) enrolled 778 patients with RCC at 215 clinical sites across 28 countries between January 3, 2017, and February 15, 2019. Patients had disease with a clear cell or sarcomatoid component and increased risk of recurrence following nephrectomy with or without metastasectomy.

The median patient age was 60 years, 73% of patients were male, and about 80% of patients were White. Overall, 79% of patients had an ECOG performance status (PS) of 0 and 21% had an ECOG PS of 1. Sixty-four percent of patients had stage T2 or T3a disease, and 22% of patients had stage T3b–c or T4 or N+ disease. Forty percent of patients were negative for PD-L1 immune cell expression on their tumors and 60% were positive.

Patients were randomized in a 1:1 ratio to adjuvant atezolizumab (390 patients) placebo (388 patients). Atezolizumab (1200 mg) or matching placebo were both administered intravenously once every 3 weeks for 16 cycles or 1 year. Investigator-assessed DFS in the intention-to-treat (ITT) population was the primary end point.

Regarding safety, Bex said, “Atezolizumab was well tolerated, and safety results were consistent with the known safety profile of atezolizumab.”

The most frequently reported grade 3/4 adverse events (AEs) were hypertension (2% in the atezolizumab arm vs 4% in the placebo arm), hyperglycemia (3% vs 2%, respectively), and diarrhea (1% vs 2%, respectively). Serious AEs occurred in 18% (69 patients) of the atezolizumab arm and 12% (46 patients) of the placebo arm. There were no patient deaths that were related to study treatment.

The study results for the trial were inconsistent with previously published data from the KEYNOTE-564 trial showing improved outcomes with adjuvant immunotherapy in patients with fully resected RCC. Specifically, the study showed that pembrolizumab (Keytruda) induced a 32% reduction in the risk of disease recurrence or death compared with placebo (HR, 0.68; 

 = .0010),3 leading to the FDA and European approvals of the immunotherapy in this setting.

Given the contrasting outcomes with immune checkpoint inhibitors, Bex said in his concluding remarks that, “Further studies are needed to clarify the role of immunotherapy in the adjuvant setting for RCC.”

1. Bex A, Uzzo R, Karam JA, et al. IMmotion010: Efficacy and safety from the phase III study of atezolizumab (atezo) vs placebo (pbo) as adjuvant therapy in patients with renal cell carcinoma (RCC) at increased risk of recurrence after resection. 

. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089

2. Kumar Pal SK, Uzzo R, Karam JA, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial [published online September 10, 2022]. 

3. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. Published online November 17, 2021. Accessed November 17, 2021. https://bit.ly/3cmJeXs

Atezolizumab given post-resection did not improve patients’ with renal cell carcinoma, at increased risk for recurrence, clinical outcomes compared to placebo. 

Adjuvant Atezolizumab Did Not Improve Outcomes in RCC

In patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (Erleada) plus androgen-deprivation therapy (ADT), potential biomarkers of overall survival (OS) outcomes have been identified in an exploratory post-hoc analysis of the phase 3 TITAN trial.

Specifically, “Detection of circulating tumor (ct)DNA or select androgen receptor (AR) and non-AR biomarkers at baseline or end of study treatment (EOST) may be associated with worse survival [with apalutamide/ADT] among patients with mCSPC,” lead study author Neeraj Agarwal, MD, Huntsman Cancer institute, and coauthors wrote in a poster they shared at the 

2022 American Society of Clinical Oncology (ASCO) Annual Meeting

Overall, the TITAN trial (NCT02489318) randomized 1052 patients with mCSPC 1:1 to receive apalutamide plus ADT or placebo plus ADT. Results of the primary and final analyses of the trial showed that adding apalutamide to ADT led to a significant benefit in OS and radiographic progression-free survival versus ADT alone.

For the biomarker analysis, Agarwal et al used next-generation sequencing to analyze ctDNA and genomic aberrations in 17 prostate cancer–related genes at baseline and at EOST. Baseline data were available for 114 patients and EOST data were available for 129 patients. Using statistical modeling, the investigators evaluated associations of ctDNA/aberrations detected at baseline and EOST with OS, as well as associations of ctDNA/aberrations detected at EOST with OS on subsequent therapies.

The investigators reported that the following aberrations occurred in ≥15% of the baseline population across both treatment arms: any genomic 

BRCA1, BRCA2, FANCA, BRIP1, HDAC2, CDK12, ATM, PALB2,

At baseline, 36% (41/114) of patients had detectable ctDNA, of which 27% (11/41) had any genomic 

 gene amplification. In this period from baseline to EOST, there was a significant increase in the presence of these biomarkers. At EOST, 75% (97/129) of patients had detectable ctDNA, of which 67% (65/97) had any genomic 

gene amplification. All of these increases were statistically significant (

There was also an increase in the most prevalent non-

aberrations at BL, however none of these increases was statistically significant:

The investigators also reported that multivariate analyses from both treatment groups showed that the baseline biomarkers of ctDNA (HR, 1.92; 95% CI, 1.11-3.31; 

 genomic aberrations (HR, 6.68; 95% CI, 1.68-26.49; 

 = .0069) were significantly associated with poor OS.

Similarly, multivariate analyses from both treatment groups also showed that the EOST biomarkers of any 

genomic aberration (HR, 1.65; 95% CI, 1.02-2.69; 

pathway aberrations (HR, 2.23; 95% CI, 1.39-3.59; 

The researchers also conducted univariate analyses of the population of patients who were treated with subsequent therapy, comprised of 106 patients who received chemotherapy and 161 patients who received hormonal therapy. The only notable findings with this assessment was that, among patients receiving chemotherapy, OS was worse among patients with 

In their poster summary, Agarwal et al noted, “The predictive value of these biomarkers for survival in mCSPC needs further confirmation.”

Agarwal N, Lucas J, Aguilar-Bonavides C, et al. Genomic aberrations associated with overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or placebo (PBO) plus androgen deprivation therapy (ADT) in TITAN. J Clin Oncol 40, 2022 (suppl 16; abstr 5066). doi: 10.1200/JCO.2022.40.16_suppl.5066

Potential biomarkers of overall survival outcomes have been identified in an exploratory post-hoc analysis of the phase 3 TITAN trial.

Survival Biomarkers Emerge for mCSPC in Phase 3 TITAN Study

Partial nephrectomy and complex masses with an imperative indication for nephron-sparing surgery enabled with the use of neoadjuvant axitinib (Inlyta) in patients with clear cell renal cell carcinoma (RCC) who have complex renal masses, acceptable safety, and functional preservation. However, no viable pathway to receive the procedure, according to interim results from the phase 2 PADRES trial (NCT03438708) presented at the 2022 AUA annual meeting.

Explaining the background of the study, lead author Kevin Hakimi, a medical student at the UC San Diego School of Medicine, said, “Up to 25% of patients presenting with renal masses have renal insufficiency or other imperative indications for nephron-conserving management. Further, although partial nephrectomy is increasingly pursued in patients with large or complex masses, a subgroup of patients with imperative indication may not initially have masses that are amenable for partial nephrectomy.”

Accordingly, Hakimiet al launched the single-arm PADRES trial to determine whether neoadjuvant therapy with the TKI axitinib could cytoreduce renal tumors and enable patients with an imperative indication to receive a partial nephrectomy.

There were 26 patients enrolled in the study, with a median age of 69.5 years. Patients had biopsy-confirmed clear cell RCC strongly indicated for partial nephrectomy with the potential for dialysis dependence if given radical nephrectomy. All patients had complex renal masses, which the study defined as a RENAL Nephrometry score in the high range of 10 to 12 and a tumor stage of cT1b to cT3M0.

There were 14 males and 12 females. The ECOG performance status was 0 for nine patients, 1 for fifteen patients, and 2 for two patients.

Patients received oral axitinib at 5 mg twice daily for 8 weeks prior to nephrectomy. The primary end point of the trial was reduction in longest tumor diameter as determined by imaging criteria. Secondary outcome measures included tumor response per RESIST criteria, feasibility of partial nephrectomy, change in RENAL Nephrometry score, survival outcomes, and post-surgical complications.

At a median follow-up of 12 months, the median reduction in tumor size was 19% (

 <.001), with a median size of 7.7 cm prior to axitinib treatment and 6.3 cm after. Axitinib also led to a significant reduction in median RENAL Nephrometry score from 11 to 10 (

 <.001). There were 9 patients (34.6%) who had a partial response per RECIST criteria and the remaining 17 patients had stable disease.

The specific tumor staging pre- vs post-axitinib was as follows: T1a, 0 vs 5 patients, respectively; T1b, 4 vs 3 patients; T2a, 2 vs 0 patients; T3a, 17 patients each; T3b, 3 vs 1 patient.

“Twenty patients initially presented with T3a/T3b disease and 9 patients were downstaged,” said Hakimi.

Regarding the safety of pre-operative axitinib, Hakimi said that 5 patients experienced grade 3 adverse events related to the treatment, consisting of hypertension (n = 3), fatigue (n = 1), and weigh loss (n = 1).

Surgical outcomes showed that 25 patients were able to complete nephrectomy, comprising 19 partial nephrectomies and 6 radical nephrectomies. Twenty four (92.3%) of the patients had negative margins. There were 6 patients who had grade 3/4 post-operative complications.

Hakimi also noted that, importantly, “Patients who underwent partial nephrectomy had preserved renal function.”

Regarding next steps, he said the PADRES trial “continues to accrue with an end goal of 50 patients.”

1. Hakimi K, Campbell S, Nguyen M, et al. Interim analysis of PADRES (prior axitinib as a determinant of outcome of renal surgery nct03438708) clinical trial. Presented during 2022 AUA Annual Meeting; New Orleans, LA. Abstract LBA01-08.

Neoadjuvant axitnib demonstrated significant reductions in tumor size and complexity, allowing for partial nephrectomy in a subgroup of patients with renal cell carcinoma.

Neoadjuvant Axitinib May Enable Partial Nephrectomy in Subgroup of Patients with RCC

Findings from the NeoAvAx trial demonstrate that the combination of the PD-L1 inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor (TKI) axitinib (Inlyta) is a promising neoadjuvant therapy for patients with high-risk, non-metastatic clear-cell renal cell carcinoma (RCC), according to findings from the NeoAvAx trial presented during the 2022 ASCO Genitourinary Cancers Symposium.

In the open-label, single-arm phase 2 trial, neoadjuvant avelumab/axitinib induced a partial response in 12 (30%) of 40 patients. Median primary tumor downsizing was 20% (range, +3.8%­ to 43.5%). Among patients with a partial response, 10 of 12 were disease-free at the study data cutoff. At a median follow-up of 23.5 months, the median overall survival (OS) and median disease-free survival (DFS) had not yet been reached. No patients had progression of their primary tumor.

“This is the first neoadjuvant trial reporting results from a combination of an immune checkpoint inhibitor (ICI) and VEGFR-TKI for locally advanced high-risk RCC,” said lead study author Axel Bex, MD, PhD, of the Netherlands Cancer Institute.“The DFS data are encouraging, supporting further evaluation, although currently there are no randomized neoadjuvant versus adjuvant ICI trials or neoadjuvant versus adjuvant ICI/VEGFR-TKI combination [trials in this setting].”

Explaining the background of the NeoAvAx trial, Bex said, “Antibodies targeting PD-1/PD-L1 combined with VEGF inhibitors are a first-line standard of care for metastatic RCC. Neoadjuvant use of these combinations may lead to downstaging and reduce the risk of recurrence.”

Overall, there were 40 patients enrolled in the trial between May 2018 and October 2021.

The median patient age was 63 years (range, 47-74), 30% of patients were female, and 70% of patients were male. The World Health Organization performance status was 0 for 30 patients and 1 for 10 patients.

Baseline cTNMwere as follows: T1b-T2b (n = 4), T3a (n = 24), T3b (n = 4), T4 (n = 8). “Ninety percent of the patients had at least a T3 stage disease and higher,” noted Bex. Biopsy grades were G1-2 (n = 27), G3-4 (n = 11), and Gx (n = 2).

Across the population, 42.5% (n = 17) of patients were clinically node positive. “Baseline lymph node diameter was a mean of 2.6 cm and the mean diameter of the primary tumor was 10.3 cm, so by no means was this a low-risk or intermediate-risk population,” explained Bex.

Study dosing was axitinib at 5 mg twice daily and avelumab at 10mg/kg every 2 weeks. The primary end point was partial response at week 12. Secondary endpoints included DFS, OS, and safety, and biomarker analysis on sequential tissue was an exploratory end point.

Overall, 13 (32.5%) patients had disease recurrence and 3 patients died of disease.

Bex said there were no new safety signals with the neoadjuvant regimen as compared with previously reported safety data for axitinib and avelumab. The majority of adverse events (AEs) were grade 1/2. There were 6 total grade 3 AEs, comprising 1 case each of hypertension, infusion-related reaction, fatigue, nausea, hand-foot syndrome, and elevated liver function tests.

Addressing the safety profile of the subsequent surgery patients received after the neoadjuvant regimen, Bex said, “Surgical adverse events were as expected in this patient population with locally advanced RCC.”

Bex also summarized the investigator findings from the exploratory biomarker analysis: “With regards to biomarkers, patients with recurrence had 

 after treatment compared to patients without recurrence. Spatial transcriptomics of post-treatment primary tumor tissue revealed focal intratumoral differences in immune signatures and we are currently investigating this further to see whether this may be one of the reasons why these patients have recurrence.”

The combination of avelumab and axitinib is currently approved by the FDA for the frontline treatment of patients with advanced RCC. The approval was based on results from the pivotal phase III 

, which showed that the combination was associated with a 31% reduction in the risk of disease progression or death compared with sunitinib (Sutent) in patients with treatment-naïve advanced RCC.

1. Bex A, Abu-Ghanem Y, van Thienen JV, et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). J Clin Oncol 40, 2022 (suppl 6; abstr 289). 10.1200/JCO.2022.40.6_suppl.289

2. FDA Approves Bavencio (Avelumab) Plus Inlyta (Axitinib) Combination for Patients With Advanced Renal Cell Carcinoma. Pfizer Oncology. Published May 14, 2019. Accessed February 20, 2022. https://on.pfizer.com/2HtdCzF

NeoAvAx trial results show that neoadjuvant avelumab/axitinib may be beneficial to patients with renal cell carcinoma. 

Neoadjuvant Avelumab/Axitinib Shows Encouraging Efficacy in Renal Cell Carcinoma

Long-term safety data pooled from 3 studies shows that darolutamide (Nubeqa) was well tolerated overall and had comparable safety and tolerability to previously reported data for the androgen receptor inhibitor in patients with metastatic castration-resistant prostate cancer (mCRPC).

The analysis from first author Egils Vjaters, MD, Pauls Stradiņš Clinical University Hospital, and coauthors was presented in a poster at the 

2022 ASCO Genitourinary Cancers Symposium

. Overall, the small study included 13 patients with mCRPC enrolled across the phase 1/2 ARADES (NCT01317641/NCT01429064), phase 1 ARAFOR (NCT01784757), and Japanese Phase 1 (NCT02363855) trials. All 13 patients had received darolutamide for more than 2 years, with a median treatment time of 38 months (range, 24-90).

The median patient age was 68 years (range, 55-81), 12 patients were White, and 1 patient was Asian. The patients were from France (n = 4), the United Kingdom (n = 3), Latvia (n = 3), Finland (n = 2), and Japan (n = 1). The median time since initial diagnosis was 32.4 months (range, 9.7-191.0).

Ten patients had normal renal function (eGFR ≥ 90 mL/min) at baseline and 3 patients had mild renal impairment (eGFR ≥ 60 to < 90 mL/min). Similarly, 10 patients had normal hepatic function at baseline and 3 had mild hepatic impairment. There were 12 patients with a baseline ECOG performance status (PS) of 0, and 1 patient with a baseline PS of 1. Nine patients had a Gleason score ≥ 7 and the remaining 3 patients had a Gleason score of < 7. The median baseline PSA was 18.1 µg/L (range, 4.6-53.6).

Initial treatment patients received for their primary tumor included chemical castration (n = 7), radiotherapy (n = 4), hormonal therapy (n = 1), and prostatectomy (n = 1). Prior and concomitant anticancer therapy patients received before the start of the study treatment included androgen-deprivation therapy (n = 13), bicalutamide (n = 10), triptorelin acetate (n = 6), goserelin acetate (n = 4), leuprorelin acetate (n= 3), cyproterone acetate (n = 3), degarelix acetate (n = 2), and abiraterone acetate (n = 1). There were no patients who had received sipuleucel-T (Provenge), docetaxel, radium-223 (Xofigo), cabazitaxel (Jevtana), or mitoxantrone.

Regarding dosing, the 8 patients from the ARAFOR study and the 1 patient from the Japanese Phase 1 trial received darolutamide at 600 mg twice daily. Among the ARADES patients, 2 were dosed at 700 mg twice daily, and 1 each received 200 mg and 300 mg twice daily, respectively.

All 13 patients experienced treatment-emergent adverse events (TEAEs). Across all reported TEAEs, regardless of whether they were categorized as drug-related, the worst severity was grade 1 or 2 for 7 patients and grade 3 for 6 patients. Six of these all-cause AEs were serious AEs and 1 led to discontinuation of darolutamide. According to the study authors, the discontinuation stemmed from a new locally advanced rectal adenocarcinoma that was not related darolutamide.

Across all of the TEAEs, there were 7 that occurred in more than 2 patients: diarrhea (n = 5), abdominal pain (n = 4), nausea (n = 4), arthralgia (n = 3), fatigue (n = 3), hematuria (n = 3), and influenza (n = 3). All of these cases were grade 1/2 except for 1 case of grade 3 nausea and 1 case of grade 3 hematuria.

There were 5 patients who experienced TEAEs considered to be drug-related. All of these drug-related AEs were grade 1, and none were serious or led to discontinuing darolutamide.

Darolutamide was approved by the FDA in 2019 for the treatment of patients with non-metastatic CRPC. According to the study authors, long-term follow-up for darolutamide in this nonmetastatic setting has consistently shown similar rates of AE-related discontinuation between darolutamide and placebo. With their study, Vjaters et al aimed to show that this positive safety/tolerability profile for darolutamide also extended to the metastatic setting.

1. Vjaters E, Fizazi K, James ND, et al. Long-term safety of darolutamide in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 40, 2022 (suppl 6; abstr 90) doi: 10.1200/JCO.2022.40.6_suppl.090

Based on pooled long-term data, the safety of darolutamide is solidified in patients with metastatic castration resistant prostate cancer.