Jason Broderick

In the phase 3 ACIS study, the addition of

apalutamide (Erleada) to abiraterone acetate (Zytiga) lead to a reduction in the risk of radiographic progression or death by 30% in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) receiving androgen deprivation therapy (ADT), according to the final analysis data presented during the 2021 Genitourinary Cancers Symposium.1

The final results showed that at a median follow-up of 54.8 months, the median radiographic progression-free survival (rPFS) was 24 months with the addition of apalutamide compared with 16.6 months with placebo plus abiraterone and prednisone (HR, 0.70). The data sustained the rPFS benefit with apalutamide observed at the primary efficacy analysis conducted at a median follow-up of 25.7 months: 22.6 months with apalutamide versus 16.6 months in the control arm (HR, 0.69; 

The rPFS benefit with apalutamide/abiraterone was sustained across prespecified subgroups. “Notably, the subgroups of patients aged 75 years or older and patients with visceral metastasis both favored the combination versus abiraterone/prednisone alone,” said principal investigator Dana Rathkopf, MD, medical oncologist, Memorial Sloan Kettering Cancer Center.

Although the study met its primary end point with a statistically significant rPFS benefit in the apalutamide arm, analyses of secondary end points showed no significant difference in outcomes between the study arms with secondary outcome measures, including overall survival (OS), time to initiation of cytotoxic chemotherapy, pain progression, and chronic opioid use.

The double-blind phase 3 ACIS study included 982 patients with chemotherapy-naïve mCRPC who received ADT. Baseline characteristics were well balanced between the 2 treatment arms. Overall, the median patient age was 71 years, about 53% of patients had a Gleason score greater than 7, the median prostate-specific antigen (PSA) level was about 32 ng/mL, and all patients had an ECOG performance status of 0 (68%) or 1 (32%).

“Approximately 10% of patients had lung metastases and 4% had liver metastases in both arms. Bone, lymph node, and soft tissue disease were equally distributed, as well,” said Rathkopf.

Patients were randomized 1:1 to apalutamide (n = 492) or placebo (n = 490) plus abiraterone and prednisone. All patients remained on continuous ADT. Patient randomization occurred between December 10, 2014, and August 30, 2016.

At the final analysis, 79.5% of patients in the apalutamide/abiraterone arm had a PSA decline of 50% or greater compared with 72.9% in the control arm (

 = .015). Also, 24.6% versus 19.2% of the 2 arms, respectively, had undetectable PSA (<0.2 ng/mL) at any time during treatment (

 = .040). However, the improved PSA decline with the apalutamide/abiraterone combo did not translate into a significant benefit in median time to PSA progression at 13.8 months versus 12 months in the control arm (

The median OS was 36.2 months with apalutamide/abiraterone versus 33.7 months in the control arm (

 = .498). The time to initiation of cytotoxic chemotherapy was 36.1 months versus 34.2 months, respectively (

= .509). The times to chronic opioid use and pain progression were 47 months versus 53.3 months (

 = .500) and 21.8 months versus 26.5 months (

“After discontinuing treatment on the ACIS trial, two-thirds of patients [across the trial] received subsequent life-prolonging therapies,” said Rathkopf. Among these treatments, docetaxel was received by about 70% of patients and enzalutamide (Xtandi) was received by about 20% of patients.

Regarding toxicity, no new safety signals were reported compared with previous reported studies of apalutamide. About two-thirds (63.3%) of patients in the apalutamide arm experienced treatment-emergent adverse events (TEAEs), compared with 56.2% of patients in the control group.

Several grade 3/4 TEAEs were more common in the apalutamide/abiraterone combination arm compared with the control arm: hypertension (20.6% vs 12.5%), fatigue (4.7% vs 3.9%), cardiac disorders (9% vs 5.7%), fall (3.3% vs 0.6%), skin rash (4.5 percent vs. 0.4 percent), seizures (0.2% vs 0), and fractures and osteoporosis (4.1% vs 1.4%).

Also of note, as measured by the Functional Assessment of Cancer Therapy–Prostate (FACT-P Total), quality of life was comparable between the apalutamide/abiraterone and control arms.

In her concluding remarks, Rathkopf noted that there was a trend toward better OS outcomes with the apalutamide/abiraterone combination in certain prespecified biomarker subgroups, such as luminal histology or high androgen activity.

“Future studies will be need to confirm these observations,” said Rathkopf.

The androgen receptor inhibitor apalutamide is currently approved by the FDA for the treatment of patients with nonmetastatic CRPC. The CYP17 inhibitor abiraterone has FDA-approved indications for use in combination with prednisone in patients with metastatic CRPC and metastatic high-risk castration-sensitive prostate cancer.

Rathkopf DE, Efstathiou E, Attard G, et al. Final results from ACIS, a randomized, placebo (PBO)-controlled double-blind phase 3 study of apalutamide (APA) and abiraterone acetate plus prednisone (AAP) versus AAP in patients (pts) with chemo-naive metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2021 Genitourinary Cancers Symposium. February 11-13, virtual. Accessed February 11, 2021. http://bit.ly/3tPysjZ

Articles

In the phase 3 ACIS study, the addition of apalutamide to abiraterone acetate lead to a reduction in the risk of radiographic progression or death by 30% in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer receiving androgen deprivation therapy. 

Apalutamide/Abiraterone Extends rPFS in Metastatic Castration-Resistant Prostate Cancer

Treatment with mitomycin-containing reverse thermal gel (Jelmyto), led to complete responses (CRs) in over 50% of patients with low-grade upper tract urothelial carcinoma (UTUC), which were maintained at 1 year, final results from the pivotal phase 3 OLYMPUS trial show.

Data for a key study secondary outcome measure reported at the 21st Annual Meeting of the Society of Urologic Oncology (SUO) showed that 56.1% of patients who achieved a CR to Jelmyto maintained that response at 12 months. This translated to an 81.8% probability of maintaining a CR at the 12-month visit.

Of note, maintenance therapy was allowed by the study protocol; however, it was modified by study investigators and there was no evidence that maintenance treatment enhanced the durability of patient responses.

The durability data from the final analysis sustained the positive primary efficacy results from OLYMPUS.

 The primary data showed that 59.2% (n = 42) of the 71-patient intent-to-treat (ITT) population achieved a CR. Eight patients had a partial response. Additionally, 20 (58.8%) of 34 patients considered unresectable at baseline by the treating urologist achieved a CR.

These primary data supported the April 2020 FDA approval of Jelmyto as the first therapy to treat patients with low-grade UTUC.

“[Jelmyto] is an innovative [treatment] and the first approved kidney-sparing approach for patients with low-grade UTUC, including for those whose tumors are difficult to treat endoscopically,” said presenting author Surena F. Matin, MD, The University of Texas MD Anderson Cancer Center in Houston.

The open-label, single-arm, phase 3 OLYMPUS trial included patients from 24 academic centers in the United States and Israel. To be eligible for enrollment, adult patients had to have treatment-naïve or recurrent disease, 1 or more measurable papillary low-grade tumors 15 mm or smaller, and a wash urine cytology sampled from the pyelocaliceal system showing the absence of high-grade disease.

Patients received 6 once-weekly intravesical instillations with a retrograde catheter to the renal pelvis and calyces. Primary disease evaluation occurred 4 to 6 weeks following the completion of treatment. The study defined CR using 3 components: negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy.

Seventy-one patients received at least 1 dose of treatment. The most commonly occurring adverse events (AEs) were ureteric stenosis (44%), urinary tract infection (32%), hematuria (32%), flank pain (31%), and nausea (25%).

“Ureteric obstruction may be associated with an increasing number of doses/procedures,” said Matin. Ureteric stenosis was the most common obstruction event and was reported after a median of 6 instillations.

Matin said anecdotal reports from study investigators suggested that, “At initial development of ureteral narrowing, stricture formation might be mitigated by treatment holiday and steroid therapy.”

There were 5 patient deaths; however, none were determined by investigators to be related to the study treatment or study procedure. All deaths occurred at least 30 days following the final dose of study treatment.

1. Lerner S, Matin S, Kleinmann N, et al. Durability of response to chemoablative treatment of low-grade upper tract urothelial carcinoma with a mitomycin-containing reverse thermal hydrogel: Final results of the OLYMPUS trial. Presented at: 21st Annual Meeting of the Society of Urologic Oncology; December 2-5, 2020; Virtual. Abstract 16

2. Kleinmann N, Matin SF, Pierorazio PM, et al. Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial.

. 2020;21(6):776-785.doi:10.1016/S1470-2045(20)30147-9

Treatment with mitomycin-containing reverse thermal gel, led to complete responses in over 50% of patients with low-grade upper tract urothelial carcinoma, which were maintained at 1 year, final results from the pivotal phase 3 OLYMPUS trial show.










Jelmyto Induces Durable Responses in Patients With Low-Grade Upper Tract UC

Treatment with MK-6482, an investigational HIF2α inhibitor, demonstrated durable efficacy as treatment of patients with Von Hippel-Lindau (VHL)-associated renal cell carcinoma (RCC) and non-renal lesions, according to phase 2 data presented during the 21st Annual Meeting of the Society of Urologic Oncology (SUO).

At a median follow-up of 68.7 weeks (range, 18.3-104.7), the objective response rate (ORR) in RCC lesions among 60 evaluable patients was 36.1%, comprising 22 confirmed partial responses (PRs). There were also 7 unconfirmed PRs. Overall, 91.8% (n = 56) of patients had at least some decrease in the size of target lesions.

The median time to response in renal tumors was 31 weeks, although responses were observed as long as 61 weeks after the start of therapy. The median duration of response had not yet been reached and the progression-free survival rate at 52 weeks was 98.3%.

Thirty-eight (62.3%) patients reached stable disease, 1 patient was not evaluable for response, and 0 patients had progressive disease.

“Promising clinical activity was observed with MK-6482 in treatment-naïve patients with VHL-associated RCC,” said lead study author Ramaprasad Srinivasan, MD, PhD, Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland.

Key eligibility criteria for the open-label phase 2 study (NCT03401788) included a confirmed diagnosis of VHL disease (based on germline mutation), at least 1 measurable RCC tumor, and an ECOG performance status of 0 or 1. Prior systemic anticancer therapy was not allowed and patients with metastatic disease were excluded from enrollment.

Overall, the study included 61 patients with a median age of 41 years (range, 19-66). Thirty-two (52.5%) patients were male, and 29 (47.5%) were female. Fifty patients had an ECOG performance status of 0, 10 patients had a performance status of 1, and 1 patient had a performance status of 2. In addition to renal tumors, all 61 patients had pancreatic lesions, 43 patients had brain hemangioblastomas, and 16 patients had retinal lesions.

Patients received 120 mg of oral MK-6482 once daily. Tumors were evaluated at initial screening and then every 12 weeks. The primary end point was ORR by central review, with secondary end points including ORR in non-RCC lesions, duration of response in RCC and non-RCC lesions, and safety.

At a minimum follow-up of 60 weeks, 56 (91.8%) patients remained on treatment.

Clinical activity with MK-6482 was observed in non-RCC lesions. The confirmed ORR in pancreatic lesions was 63.9%, including 4 complete responses. The confirmed ORR in brain hemangioblastomas was 30.2%, with a CR rate of 11.6%. Also, 11 (68.8%) of 15 patients with retinal lesions demonstrated improvement in these lesions, with the 4 other patients reaching stable disease.

Safety data showed that 60 of the 61 patients had at least 1 treatment-related adverse event (TRAE). The most common all-cause AE was grade 1/2 anemia, occurring in 51 (83.6%) patients. Eight (13.1%) patients had a grade 3 TRAE. Four (6.6%) patients had grade 3 anemia.

There were no grade 4/5 TRAEs. There was 1 discontinuation due to a TRAE (grade 1 dizziness).

Srinivasan R, Donskov F, IIiopoulos O, et al. Oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease–associated clear cell renal cell carcinoma: evaluation of RCC and non-RCC disease. Presented at: 21st Annual Meeting of the Society of Urologic Oncology; December 2-5, 2020; Virtual. Abstract 10

Treatment with MK-6482, an investigational HIF2α inhibitor, demonstrated durable efficacy as treatment of patients with Von Hippel-Lindau-associated renal cell carcinoma and non-renal lesions, according to phase 2 data presented during the 21st Annual Meeting of the Society of Urologic Oncology.

Novel HIF-2α Inhibitor Achieved Durable Responses in VHL-Associated RCC

In a subgroup of patients with high-grade, BCG-unresponsive non-muscle invasive bladder cancer (NMIBC), the novel intravesical gene-mediated therapy nadofaragene firadenovec maintained its efficacy, according to a poster shared during the 21st Annual Meeting of the Society of Urologic Oncology (SUO).

For their subgroup analysis, the investigators assessed data from a pivotal phase 3 study (NCT02773849) of nadofaragene firadenovec. A separate paper also presented during the meeting examined the incidence and time to cystectomy among patients enrolled in the same pivotal trial.

Overall, the multicenter, open-label, repeat-dose phase 3 study accrued 157 patients with high-grade, BCG-unresponsive NMIBC at 33 clinical sites in the United States. Nadofaragene firadenovec was administered by catheter as a single dose into the bladder. Those patients without recurrence received repeat doses at 3, 6, and 9 months.

In the overall study population of 157 patients, the median age was 71 years, 82% were male, and the median time from initial bladder cancer diagnosis was 18 months. Patients’ disease stages at study entry were CIS only (81 patients), Ta (35 patients), Ta + CIS (21 patients), T1 (15 patients), and T1 + CIS (5 patients). The median number of prior lines of therapy was 3 and the median number of prior BCG courses was 2.

The study met its primary end point with nadofaragene firadenovec achieving a complete response (CR) rate of 53.4% at 3 months in a subgroup of patients with carcinoma in situ with or without concomitant high-grade Ta or T1 disease (CIS ± Ta/T1). The 12-month CR rate was 24.3% and the median duration of CR was 9.69 months in these patients.

The 2 posters presented during the SUO meeting were intended to further examine the extent of nadofaragene firadenovec’s benefit in patients with NMIBC.

Among all patients, the 24-month cystectomy-free survival rate was 64.5%. Overall, 40 (26.5%) patients underwent cystectomy, including 30 patients with CIS ± Ta/T1 histology and 10 patients with high-grade Ta/T1 disease. The median time to cystectomy was 8.87 months and 8.31 months, respectively.

The median time to cystectomy among patients achieving a CR in the CIS ± Ta/T1 group was significantly longer than those not reaching CR, at 11.35 months versus 6.36 months, respectively (

 =.0432). Among patients with high-grade Ta/T1 histology, those without high-grade recurrence at month 3 had a median time to cystectomy of 12.42 months compared with 5.31 months in patients who had high-grade recurrence at that timepoint (

“Nadofaragene firadenovec is an effective bladder-sparing treatment for patients with HG BCG-unresponsive NMIBC as demonstrated by lower rate of cystectomy and longer median time to cystectomy,” lead study author, Vikram M. Narayan, MD, Emory University, Winship Cancer Institute, Atlanta, Georgia, and coauthors wrote in their study conclusion.

Subgroups analyses of the 157 patients showed that response rates in patients in the CIS ± Ta/T1 group or in the high-grade Ta/T1 group did not show significant differences between age groups, males and females, 3 or fewer or more than 3 prior lines of therapy, BCG-refractory versus BCG-relapsed, 0 or 1 or more prior non-BCG regimens, and 3 or fewer or more than 3 prior courses of BCG.

For all except 1 subgroup, there were also no significant differences in the subpopulations regarding duration of response. However, in the CIS ± Ta/T1 cohort, the duration of response was significantly longer in patients who had received less than 3 courses of prior BCG (12.68 months) versus those who had received more than 3 courses (4.96 months; 

The safety analysis for the study included all 157 patients. The majority of commonly reported treatment-related adverse events (TRAEs) were short-lived (median duration, 1-2 days). The exceptions were fatigue and frequency of micturition, with median durations of 11 and 41 days, respectively. TRAEs led to treatment discontinuations in 4 patients.

“Nadofaragene firadenovec represents a potential novel treatment option for patients with high-grade BCG-unresponsive NMIBC that advances the current treatment paradigm,” Narayan et al wrote in their conclusion.

1. Narayan V, Boorjian S, Mehrdad A, et al. Low rate of cystectomy and delayed median time to cystectomy among patients who achieved complete response with nadofaragene firadenovec. Presented at: 2020 SUO Annual Meeting. December 2-5, 2020; Virtual. Abstract 38.

2. Narayan V, Boorjian S, Mehrdad A. Subgroup analyses of the phase 3 study of intravesical nadofaragene firadenovec in patients with high-grade, BCG-unresponsive nonmuscle invasive bladder cancer (NMIBC). Presented at: 2020 SUO Annual Meeting. December 2-5, 2020; Virtual. Abstract 23.

In a subgroup of patients with high-grade, BCG-unresponsive non-muscle invasive bladder cancer, the novel intravesical gene-mediated therapy nadofaragene firadenovec  maintained its efficacy, according to a poster shared during the 21st Annual Meeting of the Society of Urologic Oncology.

Jason Broderick | Authors

Articles

Apalutamide/Abiraterone Extends rPFS in Metastatic Castration-Resistant Prostate Cancer

Jelmyto Induces Durable Responses in Patients With Low-Grade Upper Tract UC

Novel HIF-2α Inhibitor Achieved Durable Responses in VHL-Associated RCC

Nadofaragene Firadenovec Demonstrates Continued Efficacy Across Subgroups in BCG-Unresponsive NMIBC