Nichole Tucker

Findings from the phase 2 SAKK 08/16 trial shared during the 2021 ESMO Congress showed that maintenance therapy with darolutamide (Nubeqa) led to a statistically significant but clinically modest progression-free survival (rPFS) and event-free survival (EFS) benefit in pretreated patients with metastatic castration-resistant prostate cancer (mCRPC).

Patients had received at least 1 novel hormonal agent and had non-progressive disease after subsequent treatment with taxane-based therapy. The study met its primary end point and 1 secondary end point. The treatment was also found to be tolerable in patients.

The introduction of NHAs has led to an evolution in the prostate cancer treatment paradigm. Based on the signal of efficacy with NHAs, and the survival observed with darolutamide in 2 prior studies investigators hypothesized that progression of disease might be delayed with an immediate switch to darolutamide in patients with disease stabilization under chemotherapy following pretreatment with another NHA.

“We have heard a lot about the changing treatment landscape in mCRPC in the past years and so many different agents have been introduced, and however the optimal treatment sequence remains unclear. darolutamide is an androgen receptor antagonist who has a distinct structure with potentially fewer side effects due to decreased blood-brain barrier penetration,” said Richard Cathomas of Kantonsspital Graubünden, during the ESMO presentation.

In the randomized placebo-controlled double-blind SAKK 08/16 trial, 92 patients were included and randomized 1:1 at 26 centers across Switzerland, Italy, Spain, and France to receive darolutamide 600 mg twice daily or matching placebo starting 2 to 8 weeks after the end of taxane-based therapy.

Patients with stratified by country, WHO performance status, prior therapy, site of metastases, and planned start of study treatment following taxane-based therapy.

At baseline, the darolutamide had a median age of 71 years (range, 56-81). The WHO performance score in the group was 0 in 100% of patients. Sites of metastasis included bone (87%), lymph node (51%), liver (2%), and lung (2%). The majority of the darolutamide arm (53%) had a Gleason score between 8 and 10. Finally, the time from the end of taxane to the start of darolutamide was 35 days or more in 51% of patients.

In the placebo arm, the median age was 72 years (range, 55-87). Ninety-eight percent of patients in the control arm had a WHO performance score of 0. Metastatic sites were the same as the darolutamide arm with 89% of patients having bone metastases, 51% having lymph node metastases, and 2% and 4% respectively having liver or lung metastases. Also, mirroring the darolutamide arm, 53% of patients in the placebo arm had a Gleason score between 8 and 10. Following taxane-based therapy, 53% of patients in the control arm started placebo after 35 days or more.

Looking at prior NHA therapy in the darolutamide arm compared with the placebo arm, 60% of patients in each group received prior abiraterone (Zytiga) and 31% received enzalutamide (Xtandi). Also, 9% of patients in each arm received both. Largely, response to previous treatment included partial responses (PRs) including in 24% of the experimental arm versus 33% of the control arm. Further, 36% of the darolutamide arm versus 38% of the control arm achieved stable disease (SD) on their prior therapy.

Prior taxane therapy was also acknowledged at baseline and the information showed that 96% of the darolutamide arm received docetaxel compared with 87% of the placebo arm, and 4% received cabazitaxel versus 13%, respectively. Although best responses to taxane therapy were complete responses (CRs), most patients had a PR, including 29% of the darolutamide arm and 42% of the control arm. SD was achieved with taxane therapy in 69% compared with53%, respectively.

In addition to assessing rPFS at 12 weeks, the study’s secondary end points included rPFS, EFS, overall survival (OS), prostate-specific antigen response of 50% (PSA50), and safety determine by adverse events (AEs).

The study was 80% powered to detect improvement in rPFS at 12 weeks with darolutamide. At a median follow up of 18 months, the 12-months rPFS with darolutamide was 64.7% (95% CI, 47.6%-77.5%) compared with 52.2% (95% 36.1%-66.1%) in the placebo arm (

 =.127). The result was 0.15 below the significance threshold.

The median rPFS in the darolutamide arm was 5.5 months compared with 4.5 months in the placebo arm (HR, 0.54; 95% CI, 0.32-0.91; log-rank 

 =.017). In terms of EFS, the median observed in the darolutamide arm was 5.4 months versus 2.9 months with placebo (HR, 0.46; 95% CI, 0.29-0.73; log-rank 

 =.001). The median OS was 24.0 months with darolutamide compared with 21.3 months in the placebo arm (HR, 0.62; 95% CI, 0.3-1.26; log-rank 

Further efficacy results from SAKK 08/16 showed that PSA50 responses were achieved in 22% of the patients treated with darolutamide versus 4% of those treated with placebo (

 =.014). Notably, 30% PSA response was observed in 31% versus 9%, respectively, and 90% PSA response was seen in 2% of the darolutamide arm. The median duration of PSA response observed with darolutamide was 7.7 months compared with 2.8 months in the placebo arm.

Cathomas also explain subgroup outcomes on darolutamide versus placebo during his presentation. “We did a subgroup analysis, evaluating rPFS and OS. According to the response to the latest NHA therapy for patients who had a CR or PR two prior abiraterone or enzalutamide, rPFS and OS were much better on darolutamide than on placebo, whereas this was not the case if the patients had only stable disease or progressive disease on the latest NHA therapy.”

The safety analysis showed that treatment-related AEs were mild, and occurrences were similar between the 2 treatment arms. In the darolutamide arm 26% of the event were grade 1 compared with 22% in the placebo arm. The most common treatment-related AE were grade 1 fatigue, and anorexia, which occurred in 11% of the darolutamide arm versus 20% in the placebo arm and 2% versus 4%, respectively.

Results from the SAKK 08/16 trial provide proof of concept for immediate switch to darolutamide maintenance following taxane-based therapy with at least 1 NHA. Further, the data signal that response to NHA may be predictive of benefit from maintenance after NHA and taxane-based therapy in patients with mCRPC. According to Cathomas, the results are hypothesis-generating for a phase 3 clinical trial.

1. Cathomas R, Procopio G, Hayoz S, et al. Darolutamide maintenance in metastatic castration resistant prostate cancer (mCRPC) previously treated with novel hormonal agents (NHA) and non-progressive disease after subsequent treatment with a taxane: A randomized double-blind placebo-controlled phase II trial (SAKK 08/16). Presented at: 2021 European Society for Medical Oncology Congress. September 16-21, 2021. Abstract LBA26.

Articles

Patients had received at least 1 novel hormonal agent and had non-progressive disease after subsequent treatment with taxane-based therapy.

Darolutamide maintenance shows promise in pretreated mCRPC

In July 2021, the FDA granted a standard approval to enfortumab vedotin-ejfv (Padcev) for the treatment of patients with bladder cancer, based on findings from the EV-301

The antibody-drug conjugate is specifically approved for use in patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and platinum-containing chemotherapy; or patients who are ineligible for cisplatin-containing chemotherapy and have previously received 1 or more prior lines of therapy.

lead EV-301 trial author Thomas Powles, MBBS, MRCP, MD, professor of Genitourinary Oncology, lead for Solid Tumour Research at Barts Cancer Institute, Director of Barts Cancer Institute, London, United Kingdom, discusses findings from the pivotal study and where enfortumab vedotin fits in the bladder cancer treatment paradigm. 

Can you describe what outcomes look like currently for patients with locally advanced or metastatic urothelial carcinoma who progress after platinum-containing chemotherapy and on PD-1/PD-L1 regimens?

The standard treatment for metastatic urothelial cancer is to give platinum-based therapy predominantly given as a first-line treatment. And then in sequence with immune checkpoint inhibitors, maintenance avelumab [Bavencio] is a standard of care. Some individuals get second-line immunotherapy instead. So, we're sequencing chemotherapy and immunotherapy together. After progression occurs on those 2, there's a lot of uncertainty around treatment options, so we tend to rechallenge with chemotherapy then test some patients for FGF alterations. Overall, the data are limited for this patient group, and so it's an area where we need to develop new drugs.

What had been observed previously with enfortumab vedotin that led you to evaluate its use in this patient population?

Enfortumab vedotin is an antibody-drug conjugate targeting NECTIN-4, which is expressed on the vast majority of urothelial cancers. The payload is called MMAE, which is a microtubule disrupting agent. The drug is being tested in patients who have cancers that have progressed on chemotherapy and immune checkpoint inhibitors, and it has a response rate of about 40%, leading to accelerated FDA approval in 2019. The purpose of the randomized phase 3 EV-301 study was to test enfortumab vedotin against standard chemotherapy in a randomized phase 3 manner.

Can you discuss the results of this study?

This is a 650-patient study, which is robust, and it showed a significant survival advantage for enfortumab vedotin versus chemotherapy. The chemotherapy choice was docetaxel, which [is] standard. The hazard ratio was 0.70, which was statistically significant, suggesting or showing a 30% reduction in the risk of death. The overall survival in the enfortumab vedotin arm was approximately 13 months, which is long in this setting.

The response rate was 40% versus 18%, respectively. The percent and the hazard ratio for [progression-free survival] also favored enfortumab vedotin significantly, so that the efficacy signal was consistent, which is really important.

When I give this drug to my patients, this is reinforced, we see great responses and we see patients’ pain reducing with therapy. So, it’s a very active therapy in urothelial cancer.

Can you describe the toxicity profile of enfortumab vedotin as observed during the EV-301 study?

The toxicity profile is manageable. In fact, the adverse event profile showed that the percentage of grade 3 or 4 adverse events were about 50% in both groups. However, the antibody-drug conjugate had a different adverse event profile compared to standard chemotherapy. We looked out for neuropathy, skin toxicity, and hyperglycemia, particularly, which require attention. And we need to look at those while we're treating our patients. Some patients, indeed, require dose reductions or dose delays because of that. But overall, when you look at this, you say this is a new class of drug opening a new chapter in urothelial cancer…We're showing a drug with a very consistent [safety profile] with a high efficacy signal. I think this is going to be a big change for patients with bladder cancer over the next 10 years.

How do you envision this agent changing practice?

I think this is going to make a massive difference. I think it's going to be a standard of care. I think, for me, the standard of care currently is platinum-based chemotherapy and maintenance avelumab, and if [there is] progression, enfortumab vedotin is what we’ll use in the second line.

1. Powles T, Rosenberg JE, Sonpavde G, et al. Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. 

. 2021;31(suppl 6:abstr 393). doi: 10.1200/JCO.2021.39.6_suppl.393

Thomas Powles, MBBS, MRCP, MD, discusses where enfortumab vedotin fits in the bladder cancer treatment paradigm. 

Dr. Powles discusses the role of enfortumab vedotin in bladder cancer

The first patient has been treated in a phase 1 study of the novel PSMA-targeted agent ARX517 in patients with prostate cancer and other PSMA-expressing solid tumors, according to Ambrx, the developer of the investigational antibody-drug conjugate (ADC).

ARX517 joins a burgeoning PSMA pipeline that continues to expand as researchers aim to achieve similar success as 

177Lu-PSMA-617 reached in the phase 3 VISION trial.

The ADC first demonstrated promise in preclinical models for prostate cancer when the pharmacokinetics (PK) and the toxicity profile were adequate in both enzalutamide (Xtandi)-sensitive and -resistant tumors. Now, the multicenter, open-label, dose-escalation phase 1 study (APEX-01; NCT04662580) will assess the safety, PK, and antitumor activity of the agent in patients with PSMA-expression prostate, pancreatic, lung, and ovarian cancers.

“I am excited to announce that we dosed our first patient in our phase 1 trial, and thus have taken the first steps in evaluating the potential clinical benefit of ARX517 in cancer patients with tumors overexpressing PSMA,” Feng Tian, PhD, chairman of the board, president, and chief executive officer of Ambrx, stated in a press release. “ARX517 is the second ADC in our internal pipeline to enter the clinic...”

APEX-01 will enroll approximately 76 patients who will be divided into 6 dose cohorts and evaluated in 2 parts. The doses of ARX517 in the study will range from 0.32 mg/kg to 2.0 mg/kg. At all dose levels evaluated, patients will receive treatment every 3 weeks by intravenous infusion. The number of patients included in part 2 of the study will not exceed 40, according to Ambrx.

Safety/tolerability is the key primary end point of the study in part 1 along with determining the maximum-tolerated dose of ARX517 and establishing the recommended phase 2 dose (RP2D). In part 2, the primary end point of the study is to further assess the safety and tolerability of ARX517 at the RP2D. PK and the presence of anti-drug antibodies from baseline, during treatment, and at follow-up are the secondary end points of the study. Investigators will also explore surrogate biomarkers during the study, including circulating tumor cells, PSA, and imaging.

The study is actively enrolling male patients aged 18 years or older with pathologically confirmed adenocarcinoma of the prostate and other solid tumors. All patients are required to have metastatic disease by computed typography, an ECOG performance status of 0 or 1 at screening, adequate organ function, a life expectancy of at least 6 months at screening and have discontinued any radiotherapy 4 weeks prior to the start of the study in order to be eligible for enrollment.

Patients with prostate cancer must meet all the overall inclusion requirements but also be on ongoing hormone therapy, be previously treated with an FDA-approved drug for the treatment of metastatic castration-resistant prostate cancer, have disease progression, and have discontinued any non-steroidal anti-androgens 4 weeks prior to joining APEX-01.

The first recruitment site for the first-in-human study of ARX517 in PSMA-expressing solid tumors is the Urology Cancer Center of the XCancer Research Network located in Omaha, Nebraska. The site study lead is Luke Nordquist, MD, FACP.

1. Ambrx announces first patient dosed in a phase 1 trial for ARX517, an ADC in development to treat PSMA expressing tumors. News release. August 3, 2021. Accessed August 3, 2021. https://bit.ly/3ChmDaH.

ARX517 is being explored in patients with prostate cancer and other PSMA-expressing solid tumors.

Antibody-drug conjugate ARX517 joins rapidly expanding PSMA pipeline

Results from a pooled analysis of frontline treatment in metastatic renal cell carcinoma (mRCC) provided early evidence of a differential overall survival (OS) benefit between patients with favorable-risk disease compared to patients with intermediate/poor-risk disease.

The data specifically showed that among favorable-risk patients, OS was not improved with first-line immunotherapy combinations compared with upfront sunitinib (Sutent).

“We know the possible differential benefit is larger for the combined intermediate/poor-risk group, compared to the favorable risk group. The caveat is that follow-up is ongoing in each study, therefore the results and conclusion from this analysis are exploratory, noted Daniel Lee, MD, PhD of the FDA, during his presentation.

Across all mRCC risk groups, clinical trial data have shown that the outcomes are consistent for anti-VEGF therapy. For immunotherapy combinations, however, the low number of patients with favorable risk who are included in the analyses makes the outcomes observed less reliable. Although investigators are uncertain about the benefit of combination immunotherapy in this patient population, they did hypothesize that outcomes may differ and therefore studied the matter further.

Data from 3447 patients were pooled from 4 randomized phase 3 clinical trials. One of the trials combined 2 immunotherapy agents, and the 3 others studied combinations of immunotherapy and anti-VGF therapy. Utilizing an International Metastatic RCC Database Consortium (IMDC) risk model, each patient assessed was classified as either intermediate/poor risk or favorable risk. Then, Kaplan-Meier and Cox Proportional Hazards methods were used to compare the OS between the immunotherapy combination to the sunitinib control arm.

In total, 422 patients were treated with an immunotherapy combination in the favorable risk group and 404 were treated with sunitinib. The death rate in the arms was 22.0% versus 23.0%, respectively. The median OS was not reached (NR) in either arm (95% CI, NR, NR). The hazard ratio (HR) was 0.953 (95% CI, 0.72-1.27).

In the intermediate/poor risk population, 1,308 patients received an immunotherapy combination compared 1,313 who received sunitinib. There were deaths rates in the study arms of 40.8% versus 50.9%, respectively. The median OS observed in the combination arm was 46.8 months (95% CI, 39.9 to not reached). In comparison, the median OS was 29.3 months with sunitinib (95% CI, 26.0-32.9), showing an HR of 0.696 (95% CI, 0.62-0.78).

Providing an explanation of these data, Lee stated during his presentation, “In looking at the hazard ratios, there was an absence of benefit for the favorable risk group, whereas there was a benefit in the combined intermediate poor-risk group. And looking at the survival curves, for the favorable risk there was no difference in survival, whether the patients received the combination therapy or sunitinib. In comparison, for the combined intermediate poor-risk group, there was a difference in survival, which favored the combination therapy.”

1. Lee D, Gittleman H, Weinstock C, et al. 

. 2021;39(suppl 15):4559. doi: 10.1200/JCO.2021.39.15_suppl.4559

Results from a pooled analysis of frontline treatment in metastatic renal cell carcinoma provided early evidence of a differential overall survival benefit between patients with favorable-risk disease compared to patients with intermediate/poor-risk disease.

Nichole Tucker

Articles

Darolutamide maintenance shows promise in pretreated mCRPC

Dr. Powles discusses the role of enfortumab vedotin in bladder cancer

Antibody-drug conjugate ARX517 joins rapidly expanding PSMA pipeline

Risk-group analysis offers clues to optimizing frontline I/O combos in metastatic kidney cancer