Benjamin Saylor

Darolutamide (Nubeqa) demonstrated a significantly reduced risk of metastatic progression and improved overall survival vs placebo when used as treatment for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to findings from a recent study presented at the 2022 American Society of Clinical Oncology Annual Meeting.

Previously reported findings of the phase 3 ARAMIS trial (NCT02200614) found that treatment with darolutamide significantly prolonged metastasis-free survival by nearly 2 years and reduced the risk of death by 31% vs placebo with favorable tolerability in patients with nmCRPC.

For the current study, the investigators, led by Alicia K. Morgans, MD, MPH, a genitourinary medical oncologist and the medical director of the Survivorship Program at Dana-Farber Cancer Institute in Boston, Massachusetts, conducted post hoc analyses of ARAMIS “evaluate the association between metastatic progression with prostate-specific antigen (PSA) and clinical progression and to describe the distribution of metastatic progression between groups,” according to the study’s abstract.

The investigators randomized patients 2:1 to darolutamide 600 mg twice daily or placebo while continuing treatment with androgen deprivation therapy. They performed descriptive analyses using the primary data cutoff for the double-blind period. Central review of conventional radiographic imaging every 16 weeks was used to determine post-baseline metastases.

The investigators observed metastatic progression in 130/955 patients treated with darolutamide (13.6%) vs 158/554 patients treated with placebo (28.5%). In the darolutamide arm, 46% of metastatic progression was bone only, 32% was distant lymph node only, and 22% was mixed metastatic types. In the placebo arm, 39% of metastatic progression was bone only, 40% was distant lymph node only, and 21% was mixed metastatic types.

Median time from initial diagnosis to study treatment was shorter in patients with metastatic progression (darolutamide arm, 86.2 months; placebo arm, 74.4 months) compared with the overall ARAMIS study population (86.2 and 84.2 months, respectively). For patients with metastatic progression, median PSA levels at baseline were similar between the 2 groups at 12.6 ng/mL in the darolutamide arm vs 15.1 ng/mL but were lower in the darolutamide patients before metastasis at 16.7 ng/mL compared with patients receiving placebo (48.0 ng/mL).

“Among patients with metastatic progression, PSA progression before metastasis occurred in 55.6% (160/288) of patients, occurring in fewer darolutamide vs placebo patients (45.4% vs 63.9%),” wrote the investigators in their poster.

In addition, the median time between PSA progression and metastasis was 7.0 months for darolutamide compared with 5.6 months for placebo. Pain progression before metastasis was 16.9% and 17.7% for the darolutamide and placebo arms, respectively.

“In patients with nmCRPC, darolutamide significantly reduced the risk of metastatic progression and improved overall survival compared with placebo without changing the pattern of metastatic progression….These results support the use of both imaging PSA monitoring to properly identify disease progression in patients with nmCRPC,” wrote the investigators in their conclusion.

1. Morgans AK, Sweeney C, Wallis CJD, et al. Progression patterns by types of metastatic spread, prostate-specific antigen (PSA), and clinical symptoms: Post-hoc analyses of ARAMIS. 

 2022;40(suppl 16):5044. doi:10.1200/JCO.2022.40.16_suppl.5044

2. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. 

 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671

3. Fizazi K, Shore N, Temmela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. 

 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342.

Articles

Reduced risk of metastatic progression and improved overall survival seen with darolutamide in patients with nonmetastatic castration-resistant prostate cancer.

Reduced Risk of Metastatic Progression With Darolutamide in Patients With nmCRPC

In a phase 2 clinical trial, the use of maintenance cabozantinib (Cabometyx) following chemotherapy in patients with advanced urothelial carcinoma demonstrated tolerability but did not show a significant benefit vs placebo.

Findings from the randomized, double-blind phase 2 ATLANTIS clinical trial were presented by first author Robert J. Jones, MA, PhD, MBChB, at the 2022 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.

The ATLANTIS trial included patients with advanced urothelial carcinoma who underwent 4 to 8 cycles of first-line chemotherapy, during which time they were prescreened for tissue-based biomarkers. Patients with ongoing clinical benefit after chemotherapy were offered randomization into one of several substudies based on biomarker status. Patients with a DNA repair deficiency were randomized to rucaparib (Rubraca) vs placebo, patients who were androgen receptor biomarker positive were randomized to enzalutamide (Xtandi) vs placebo, and patients who were “all biomarkers negative” received cabozantinib or placebo.

Patients in the cabozantinib arm received 40 mg once daily vs matching placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), confirmed response rates, and safety and tolerability.

Recruitment was discontinued after 61 patients were randomized due to a United Kingdom-wide recruitment hiatus beginning in March 2020 because of the COVID-19 pandemic, and also due to the presentation of data in June 2020 supporting the use of avelumab (Bavencio) in the maintenance setting.2 The trial’s power was subsequently revised to 72.3% from an original value of 90%.

Jones reported a median PFS of 13.7 weeks (80% CI, 12.1-23.3) with cabozantinib vs 15.8 weeks (80% CI, 11.3-23.6) with placebo. The HR was 0.89 in favor of cabozantinib (80% CI, 0.61-1.30, 1-sided 

= .35). Median OS was 75.5 weeks (80% CI, 43.4-117.6) with cabozantinib vs 82.9 weeks (80% CI, 58.0-117.1) with placebo. The HR was 0.80 in favor of cabozantinib (80% CI, 0.52-1.30, 1-sided 

Median duration of treatment was 13 cycles for cabozantinib vs 10 cycles for placebo. Overall response rate was 3.3% for cabozantinib vs 6.5% for placebo.

Regarding safety, adverse events seen more commonly in patients receiving cabozantinib vs placebo included fatigue (56.7% vs 32.2%, respectively; 

 = .02), hypertension (43.3% vs 12.9%; respectively, 

 =.01), nausea (30% vs 19.4%, respectively; 

= .36) and diarrhea (40.0% vs 6.5%; respectively, 

“Notably, 43% of patients receiving cabozantinib had to reduce the dose from 40 to 20 mg, although there were no treatment discontinuations due to toxicity,” said Jones, professor of clinical research at the University of Glasgow Institute of Cancer Sciences in Glasgow, Scotland.

In his concluding remarks, Jones said, “Though underpowered, this study does not support further investigation of cabozantinib alone as a maintenance therapy after platinum-based chemotherapy in unselected patients with advanced urothelial cancer.”

Jones added that negative patient selection for DNA repair deficiency and androgen receptor biomarkers may have biased interpretation of the findings.

“Future trials should consider combining novel agents with maintenance immunotherapy,” Jones said.

1. Jones RJ, Hussain SA, Birtle AJ, et al. A randomised, double blind, phase II clinical trial of maintenance cabozantinib following chemotherapy for metastatic urothelial carcinoma (mUC): Final analysis of the ATLANTIS cabozantinib comparison. 

. 2022;40(suppl 170):LBA4505. doi:10.1200/JCO.2022.40.17_suppl.LBA4505

2. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. 

. 2020;383(13):1218-1230.doi:10.1056/NEJMoa2002788

Maintenance Cabozantinib Fails to Show Significant Benefit in Advanced Urothelial Carcinoma

The use of adjuvant pembrolizumab as treatment of patients with renal cell carcinoma (RCC) who are at high risk of recurrence continued to demonstrate improved disease-free survival (DFS) compared with placebo, according to an updated analysis of the phase 3 KEYNOTE-564 trial (NCT03142334).

The findings were reported by Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School in Boston, Massachusetts during the 2022 Genitourinary Cancers Symposium in San Francisco, California.

Previously reported data from KEYNOTE-564 found that treatment with adjuvant pembrolizumab yielded a statistically significant and clinically meaningful DFS benefit versus placebo in the intent-to-treat population (HR, 0.68, 95% CI: 0.53-0.87, 

= .001).2 The 2022 GU Symposium presentation consisted of an updated efficacy and safety analysis with 30.1months of follow-up.

KEYNOTE-564 evaluated patients with RCC defined as intermediate-high risk (pT2, grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0), high-risk (pT4, any grade, N0, M0; any pT, any grade, N+, M0) and M1 no evidence of disease (NED) following surgery. Patients randomized 1:1 to receive either pembrolizumab, 200 mg every 3 weeks (n = 496) or placebo every 3 weeks (n = 498).

Median patient age was 60 years in both the treatment and placebo groups. A total of 347 patients in the pembrolizumab group were male (70.0%) versus 359 patients (72.1%) in the placebo group. Regarding risk category, 427 patients were intermediate-high risk (86.1%), 40 patients (8.1%) were high risk, and 29 patients (5.8%) were M1 NED in the treatment group versus 433 (86.9%), 36 (7.2%), and 29 (5.8%) in the placebo group, respectively. In the treatment group, there 52 patients (10.5%) in whom sarcomatoid features were present versus 414 patients (83.5%) in whom sarcomatoid features were absent, compared with 59 (11.8%) and 415 (83.3%) in the placebo group.

For the primary end point of DFS, benefit was maintained in patients receiving pembrolizumab (HR, 0.63, 95% CI: 0.50-0.80, nominal 

< .0001) and was as follows across the 3 subgroups

Intermediate-high risk: HR, 0.68 (95% CI: 0.52-0.89)

“The estimated DFS rate at 24 months was 78.3% with pembrolizumab versus 67.3% with placebo…The estimated [overall survival] rate at 24 months was 96.2% with pembrolizumab versus 93.8% with placebo,” wrote the authors.

In the primary analysis of KEYNOTE-564, presented at 24.1 months’ follow-up, 470 patients (96.3%) in the pembrolizumab group experienced an all-cause adverse event (AE) versus 452 (91.1%) in the placebo arm; in the updated findings presented at the 2022 ASCO GU Symposium, the number of patients in the pembrolizumab arm experiencing an all-cause AE was unchanged compared with 453 patients (91.3%) in the placebo arm. Grade 3-4 AEs were also very similar for the pembrolizumab arm at 24.1 months and 30.1 months with 42 patients (8.6%) and 43 patients (8.8%) respectively, compared with 3 patients (0.6%) in the placebo arm at 24.1 and 30.1 months.

“I think that this updated analysis of KEYNOTE-564 further supports adjuvant pembrolizumab as a new standard of care for patients with RCC with high risk of recurrence,” Choueiri told 

1. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: Results from 30-month follow-up of KEYNOTE-564. J Clin Oncol. 2022;40(suppl 6):abstr 290. doi:10.1200/JCO.2022.40.6_suppl.290

2. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391

Updated findings from the phase 3 KEYNOTE-564 trial may further support adjuvant pembrolizumab as a new standard of care for patients with renal cell carcinoma with high risk of recurrence.

Updates Results of Adjuvant Pembrolizumab in RCC Shows Sustained DFS Benefit

Study results show that the safety and efficacy of the androgen receptor inhibitor, darolutamide (Nubeqa) was sustained in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) with comorbidities or concomitant medications, investigators reported at the 

2022 ASCO Genitourinary Cancers Symposium

For the study, patients with nmCRPC from the 

 (NCT02200614) were randomized 2:1 to receive either darolutamide (n = 955) or placebo (n = 554) while continuing treatment with androgen deprivation therapy. At the final data cut-off date of November 15, 2019, overall survival (OS) and adverse events (AEs) were evaluated in patients with a median of 6 or fewer or more than 6 comorbidities and 10 or fewer or more than 10 concomitant medications. Comorbidities evaluated included metabolic, cardiovascular, and other (osteoarthritis and arthralgia and back pain, benign prostatic hyperplasia, constipation and gastroesophageal reflux, and renal insufficiency). Concomitant medication classes/subclasses included gastrointestinal/metabolic, cardiovascular (antihypertensives and non-antihypertensives), pain/inflammation, and urologic.

“More than 50% of the patients in the ARAMIS trial, which was a very significant number of patients…had a minimum of 6 or more comorbidities of significance,” commented study coauthor Neal D. Shore, MD, in an interview with Targeted Oncology

Specifically, 795 of the total cohort of 1509 patients had at least 6 comorbidities, and 813 patients had received at least 10 concomitant medications.

The investigators reported that in patients with at least 6 and more than 6 comorbidities, darolutamide prolonged OS compared with placebo (HR, 0.65 and 0.73, respectively). The OS benefit for darolutamide was found to be consistent in patients with metabolic, cardiovascular (CV), and other comorbid disorders (HR, range, 0.39-0.88). OS was also prolonged in patients receiving at least 10 and more than 10 concomitant medications (HR, 0.76 and 0.66, respectively). “Subgroups of [patients] receiving concomitant medications for gastrointestinal/metabolic disorders, CV disease, urologic disorders, and pain/inflammation achieved similar OS benefit with [darolutamide versus placebo] (HR range, 0.45–0.80),” wrote the authors.

Regarding AEs, 447 patients with at least 6 comorbidities (83%) and 366 patients with more than 6 comorbidities (90%) experienced any AE, versus 242 (74%) and 195 patients (88%) receiving placebo, respectively. A total of 127 patients with at least 6 comorbidities (24%) and 124 patients with more than 6 comorbidities (31%) experienced a grade 3 or 4 AE, versus 58 (18%) and 61 (28%) patients receiving placebo, respectively. A total of 43 patients with at least 6 comorbidities (8%) and 42 patients with more than 6 comorbidities (10%) experienced an AE leading to permanent study drug discontinuation, versus 20 (6%) and 28 patients receiving placebo (13%).

A total of 371 patients (77%) taking at least 10 concomitant medications and 442 patients taking more than 10 concomitant medications (95%) experienced any AE, versus 184 (68%) and 248 (91%) of patients receiving placebo, respectively. Sixty-seven patients (14%) taking at least 10 concomitant medications and 183 patients (39%) taking more than 10 concomitant medications experienced a grade 3 or 4 AE, versus 36 (13%) and 82 patients (30%) receiving placebo, respectively. Finally, 35 patients taking at least 10 concomitant medications (7%) and 50 patients taking more than 10 concomitant medications (11%) experienced an AE leading to permanent study drug discontinuation, versus 17 (6%) and 29 patients (11%) receiving placebo, respectively.

“I think what we're showing here is that the overall survival benefit, as well as the safety analysis, regardless of the number of comorbidities, was rather significant,” Shore said.

1. Fizazi K, Shore ND, Smith MR, et al. Efficacy and safety outcomes of darolutamide in patients with nonmetastatic castration-resistant prostate cancer with comorbidities and concomitant medications from ARAMIS. Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract 256.

In a subgroup analysis of the ARAMIS study, the safety and efficacy of darolutamide were not impacted by patients having comorbidities and receiving concomitant medications.

Darolutamide Remains Safe/Effective in Patients With nmCRPC and Comorbidities Receiving Concomitant Medications

Treatment with darolutamide (Nubeqa), an androgen receptor inhibitor, showed significant delay in time to locally invasive procedures and time to deterioration in health-related quality of life (HRQOL) measures in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).

For the study, investigators evaluated the effect of darolutamide on local symptom control. Specifically, they examined incidence and time to first prostate cancer-related invasive procedures, time to deterioration in health-related quality of life measures, and incidence of urinary and bowel treatment-related adverse events and their correlation with PSA decline from baseline to week 16 in patients receiving darolutamide, according to presentation given during the American Urological Association 2021 Annual Meeting .

Time to deterioration in HRQOL measures was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Prostate Cancer Module and the Functional Assessment of Cancer Therapy-Prostate (FACT-P) prostate cancer subscale.

In assessing incidence and time to first locally invasive procedures, “The results of these analyses showed that fewer patients receiving darolutamide, 4.7%, underwent locally invasive procedures, compared with patients receiving placebo, 9.6%,” said first author Neal D. Shore, MD, FACS, director of Carolina Urologic Research Center in Myrtle Beach, South Carolina. The most common procedures included catheterization, transurethral resection of the prostate, nephrostomy, and surgical excisions and resections.

Darolutamide also significantly prolonged the time to first prostate cancer-related locally invasive procedure compared with placebo (hazard ratio [HR], 0.42; 95% CI, 0.28-0.62).

“For the EORTC urinary symptom subscale, darolutamide significantly delayed the time to deterioration in quality of life for total urinary symptoms and for each individual question about urinary symptoms versus placebo,” Shore said.

The 4 questions that contributed the most to the delay in time to deterioration of HRQOL with darolutamide were:

• urinate frequently during the day (HR, 0.764; 95% CI, 0.648-0.902)

• urinate frequently at night (HR, 0.664; 95% CI, 0.559-0.790)

• pain when urinating (HR, 0.569; 95% CI, 0.441-0.734)

• urinary problems interfere with daily activities (HR, 0.748; 95% CI, 0.614-0.910).

Darolutamide was also found to significantly delay the time to deterioration of total bowel symptoms vs placebo (HR, 0.781; 95% CI, 0.664-0.918).

“For each of the 4 bowel symptom-related questions, darolutamide delayed the time to deterioration versus placebo with hazard ratios ranging from 0.87 to 0.91, but 95% confidence intervals were wide and crossed 1,” Shore said.

Regarding the FACT-P Prostate Cancer Subscale, darolutamide significantly delayed time to deterioration for total urinary symptoms as well as for each of the 3 urinary symptom questions. The time to deterioration in trouble moving bowels was not significantly affected by treatment with darolutamide, however (HR, 1.089; 95% CI, 0.0862-1.376).

In the overall study population, urinary retention occurred in 36 patients (3.8%) in the treatment arm vs 41 patients (7.4%) in the placebo arm. Dysuria occurred in 25 patients (2.6%) in the treatment arm vs 29 patients (5.2%) in the placebo arm.

“The incidences of other urinary and bowel adverse events showed minimal differences of 2% or less between treatments,” Shore said.

In addition, for patients treated with darolutamide, greater prostate-specific antigen response was associated with a lower incidence of urinary retention and dysuria.

Specifically, patients receiving darolutamide who had a PSA decline of 90% or greater from baseline to week 16 had incidences of urinary retention and dysuria of 2.2% and 0.5% respectively compared with 5.1% for urinary retention and dysuria in patients with a PSA response of less than 50%.

“In conclusion, darolutamide was associated with a reduction in locally invasive procedures and delayed time to deterioration in patient health-related quality of life with respect to urinary and bowel symptoms. No increase in urinary and bowel-related adverse events compared with placebo confirms the favorable safety profile of darolutamide. These findings demonstrate that darolutamide had a positive effect on local disease recurrence and symptom control in patients with nonmetastatic CRPC,” Shore said.

Shore S, Stenzl A, Pieczonka C, et al. Impact of darolutamide on local symptoms in patients with nonmetastatic castration-resistant prostate cancer. Paper presented at the 2021 American Urological Association Annual Meeting; September 10-13; virtual. Abstract PD34-10

Darolutamide has shown an impact on local symptoms in patients with nonmetastatic castration-resistant prostate cancer. One of the impacts was a delay in time to HRQOL deterioration. 

Darolutamide Significantly Stalls Time to Deterioration of HRQOL in Patients With nmCRPC

 metastatic castration-sensitive prostate cancer (mCSPC) treated in the phase 3 PEACE-1 study (NCT01957436), the addition of abiraterone acetate (Zytiga) and prednisone to androgen-deprivation therapy (ADT) and docetaxel improved radiographic progression-free survival (rPFS), according to initial results presented during the 2021 ASCO Annual Meeting.

The findings showed that adding abiraterone/prednisone to standard docetaxel/ADT was associated with an approximately 2.5-year absolute benefit in median rPFS in this patient population.

 mCSPC in a 1:1:1:1 ratio to standard of care (SOC), SOC plus abiraterone acetate/prednisone, SOC plus radiotherapy (RT), or SOC plus abiraterone plus RT. Initially, SOC was ADT alone, but from October 2015 onward, the use of docetaxel was permitted. This was done at the investigator’s discretion until 2017, at which point, following the publication of the LATITUDE (NCT01715285) and STAMPEDE (NCT00268476) trials, docetaxel was mandatory.

Patient stratification was based on ECOG performance status, metastatic sites, type of castration, and docetaxel status.

The 2 coprimary end points were rPFS and overall survival. Key secondary end points included castration resistance–free survival, prostate cancer–specific survival, time to next skeletal-related event, PSA response rate, quality of life, and safety.

Between November 2013 and December 2018, 1173 men were enrolled. The median patient age was 67 years (interquartile range, 60-72). High-volume disease was present in 57% of patients, with 43% of patients having low-volume disease. Median follow-up was 3.5 years.

The investigators found no interaction between the effect of local RT and that of abiraterone on rPFS, which allowed the pooling of the 2 abiraterone arms for analysis. When divided into abiraterone and SOC arms, patient characteristics were similar between the arms.

The investigators reported a median rPFS of 4.5 years in the abiraterone arm in the overall population versus 2.2 years for SOC (

< .0001). Similarly, better rPFS was observed in the abiraterone arm versus the SOC arm in the ADT plus docetaxel population (4.5 vs 2.0 years; 

<.0001). In addition, PFS including PSA progression as an event was also improved with abiraterone in both the overall population (3.8 vs 1.5 years; 

<.0001) and the ADT plus docetaxel population (3.2 vs 1.4 years; 

“Importantly, all tested subgroups pretty much seemed to benefit from the addition of abiraterone,” said lead study author Karim Fizazi, MD, PhD, head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France, and a professor of Oncology at the University of Paris-Sud.

In the docetaxel population, grade 3 to 5 toxicities that were higher in patients receiving abiraterone and docetaxel versus patients receiving docetaxel but not abiraterone included liver toxicities (6% vs 0%) and hypertension (12% vs 8%).

“It was very reassuring to see that abiraterone, even used concomitantly with docetaxel, did not increase the risk of febrile neutropenia…or other hematological toxicities related to docetaxel,” Fizazi said.

Grade 3 to 5 gastrointestinal toxicity and fatigue, which are typically associated with docetaxel, had a lower incidence in the group of patients receiving abiraterone (2% vs 4%), which Fizazi said may be due to the abiraterone cohort also receiving prednisone.

“In conclusion, adding abiraterone and prednisone to ADT plus docetaxel clearly improves radiographic PFS in men with 

 metastatic prostate cancer,” Fizazi said.

Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): First results of PEACE-1. 

 39, 2021 (suppl 15; abstr 5001). doi: 10.1200/JCO.2021.39.15_suppl.5000

In men with de novo metastatic castration-sensitive prostate cancer treated in the phase 3 PEACE-1 study, the addition of abiraterone acetate and prednisone to androgen-deprivation therapy  and docetaxel improved radiographic progression-free surviva.