Jason M. Broderick

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of darolutamide (Nubeqa) for use in combination with docetaxel and androgen deprivation therapy (ADT) for the treatment of patients with metastatic hormone-sensitive prostate cancer (mHSPC).

The oral androgen receptor inhibitor darolutamide is already approved in the United States for use in patients with mHSPC.

The CHMP’s recommendation is based on the placebo-controlled phase 3 ARASENS trial (NCT02799602), which showed that adding darolutamide to standard ADT and docetaxel boosted overall survival (OS) versus ADT/docetaxel alone in patients with mHSPC.

Results reported at the 2022 Genitourinary Cancers Symposium

 showed that at a median follow-up of 43.7 months for darolutamide plus ADT/docetaxel and 42.4 months with placebo plus ADT/docetaxel, the active therapy resulted in a 32.5% reduction in the risk of death (HR 0.68; 95% CI 0.57-0.80; 

The European Commission will now review the application for darolutamide and make a final decision on this indication in the coming months.

In the ARASENS trial, patients with cytologically confirmed metastatic adenocarcinoma of the prostate were eligible for the trial. All participants needed to be candidates for ADT and docetaxel, have an ECOG performance status of 0 or 1, and have adequate organ function.

Patients were randomized 1:1 to either 600 mg of daily darolutamide (n = 651) or matched placebo (n = 655) plus ADT/docetaxel. Factors for stratification included extent of disease (M1b/b/c) and alkaline phosphatase (ALP) levels. The primary end point was OS with secondary outcome measures of time to CRPC, time to pain progression, time for first symptomatic skeletal event (SSE), time to initiation of subsequent systemic antineoplastic therapy, and safety.

Patient characteristics were well balanced between the 2 groups. The median age was 67 years for both the darolutamide and placebo groups and most patients had a Gleason score of 8 or greater (77.6% vs 78.9%, respectively) and M1 stage (85.7% vs 86.5%) at initial diagnosis. At initial screening, patients in both groups were most likely to have M1b stage disease (79.4% vs 79.5%) and ALP levels equal to or above the upper limit of normal (55.5% each).

Median OS in the darolutamide arm was not estimable (NE; 95% CI, NE-NE) vs 48.9 months (95% CI, 44.4-NE) with placebo. Rates of OS at 48 months were 62.7% and 50.4%, respectively. The effect of active therapy was consistent across patient subgroups, including by ALP level below (HR, 0.64; 95% CI, 0.46-0.88) or above the upper limit of normal (HR, 0.69; 95% CI, 0.56-0.85), and by either de novo (HR, 0.71; 95% CI, 0.59-0.85) or recurrent (HR, 0.61; 95% CI, 0.35-1.05) metastatic disease status.

Moreover, darolutamide was associated with superior secondary outcomes despite patients in this arm receiving fewer subsequent life-prolonging systemic antineoplastic therapies (56.8%) vs the placebo arm (75.6%). Common subsequent therapies included abiraterone acetate (35.6% vs 46.9%), enzalutamide (Xtandi; 15.2% vs 27.5%), cabazitaxel (Jevtana; 18.1% vs 18.0%), and docetaxel (14.6% vs 18.0%). Notably, 66% of patients in the placebo arm went on to receive life-prolonging therapy with an AR pathway inhibitor. Time to first subsequent antineoplastic therapy was NE (95% CI, NE-NE) in the active therapy arm vs 25.3 months (95% CI, 23.1-28.8) in the placebo group (HR, 0.39; 95% CI, 0.33-0.46; 

A significant delay in time to castration-resistant disease was noted in the darolutamide vs placebo groups, at NE (95% CI, NE-NE) vs 19.1 months (95% CI, 16.5-21.8), respectively (HR, 0.36; 95% CI, 0.30-0.42; 

 <.001). Darolutamide was also associated with increased time to pain progression at NE (95% CI, 30.5-NE) vs 27.5 months (95% CI, 22.0-36.1) with placebo (HR, 0.79; 95% CI, 0.66-0.95; 

 = .01). Time to first SSE was NE in both arms, but statistically significant benefit with the darolutamide combination was noted (HR, 0.71; 95% CI, 0.54-0.94; 

Rates of treatment-emergent adverse events (AEs) were similar between arms, at 99.5% with the darolutamide regimen and 98.9% with placebo. Consistent with prior clinical experience in other settings, darolutamide had a favorable safety profile. The rates of any treatment-emergent adverse event, serious adverse event, and adverse events leading to permanent discontinuation of study treatment were similar between the darolutamide and the placebo groups.

Grade 3/4 AEs occurring with darolutamide and placebo included neutropenia (33.7% vs 34.2%, respectively), febrile neutropenia (7.8% vs 7.4%), hypertension (6.4% vs 3.2%), and anemia (4.8% vs 5.1%). After adjusting for differences in drug exposure, the was no difference in the occurrence of AEs of special interest for AR pathway inhibitors between groups, including events such as fatigue, bone fractures, rash, falls, hypertension, and cardiac disorders.

1. Positive CHMP opinion for darolutamide in combination with docetaxel for the treatment of metastatic hormone-sensitive prostate cancer. Published online and accessed January 27, 2023. https://bit.ly/3RnKihj

2. Smith MR, Hussain MHA, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. 

. 2022;40(suppl 6):abstr 13. doi: 10.1200/JCO.2022.40.6_suppl.013

3. Smith MR, Hussain MHA, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. 

. Published online February 17, 2022. doi: 10.1056/NEJMoa2119115

Articles

The application for darolutamide in the European Union is supported by findings from the phase 3 ARASENS trial.

Darolutamide nears EU approval for mHSPC

The phase 3 KEYNOTE-991 trial (NCT04191096) exploring the combination of pembrolizumab (Keytruda), enzalutamide (Xtandi), and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) has been stopped by Merck (MSD) due to futility, the company announced in a press release.

The immunotherapy pembrolizumab continues to be explored in other settings in prostate cancer.

The discontinuation of the trial follows the recommendation of an independent Data Monitoring Committee, which reviewed findings from an interim analysis showing that the addition of pembrolizumab to enzalutamide and ADT did not improve the trial’s primary end points of overall survival and radiographic progression-free survival (rPFS) compared with enzalutamide and ADT alone. Although overall toxicity was worse in the pembrolizumab arm, there were no new safety signals reported with any of the drugs.

The double-blind phase 3 KEYNOTE-991 trial had enrolled 1251 patients. Merck plans to share the data from the study at an upcoming conference.

“There is a significant unmet need for patients with advanced prostate cancer, and the outcome of this study is an important reminder that this disease remains very difficult to treat,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, stated in the press release “We are grateful to the patients and investigators for their participation in this study, and we will continue to advance our clinical development program to evaluate Keytruda-based combinations and novel candidates for patients with prostate cancer.”

Merck continues to evaluate pembrolizumab in prostate cancer in several other clinical trials, including the phase 2 KEYNOTE-365 trial (NCT02861573) and the phase 3 KEYNOTE-641 trial (NCT03834493).

Pembrolizumab does not currently have an FDA-approved indication for patients with prostate cancer; however, the drug does have a tumor-agnostic approval for the treatment of patients with tumor mutational burden–high solid tumors.

Enzalutamide is approved by the FDA for the treatment of patients with mHSPC. The approval is based on the international, double-blind ARCHES trial. The study enrolled 1150 patients with histologically verified metastatic castration-sensitive prostate cancer across North America, Europe, and the Asia-Pacific region. Patients were randomized to receive ADT plus either enzalutamide or placebo. Men with both low- and high-volume disease, as well as patients who received recent treatment with docetaxel but did not have disease progression were enrolled.

The study results reviewed by the FDA showed the median rPFS was not reached with enzalutamide plus ADT and was 19.45 months with placebo plus ADT, translating to a 61% reduction in risk of radiographic progression or death (HR, 0.39; 

 Additionally, the addition of enzalutamide was also associated with an 81% reduction in the risk of time to PSA progression (HR, 0.19; 

1. Merck Announces KEYNOTE-991 Trial Evaluating KEYTRUDA® (pembrolizumab) Plus Enzalutamide and Androgen Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer to Stop for Futility. Published online January 25, 2023. Accessed January 26, 2023. https://bit.ly/3kN77Pf

2. Xtandi (Enzalutamide) approved by U.S. FDA for the treatment of metastatic castration-sensitive prostate cancer [news release]. Pfizer. Published December 16, 2019. https://bit.ly/2tpujIV. Accessed December 16, 2019.

The double-blind phase 3 KEYNOTE-991 trial had enrolled 1251 patients.

Pembrolizumab plus enzalutamide/ADT falls short in mHSPC

Patient enrollment is now complete for the randomization component of the phase 3 SPLASH trial exploring PNT2002 in patients with metastatic castration-resistant prostate cancer (mCRPC), according to POINT Biopharma, the developer of the novel PSMA-targeted therapy.

The SPLASH trial is examining PNT2002 in patients whose tumors express PSMA and who have experienced disease progression on an androgen receptor axis–targeted therapy.

There are now more than 390 patients enrolled and randomized in the trial at locations in 55 sites across North America, Europe, and the United Kingdom. The randomization phase was launched after successful completion of the open-label dosimetry and safety run-in phase, in which all prespecified safety and efficacy criteria were met. There were 27 patients who participated in this phase.

“We are proud to have reached this important milestone for the PNT2002 program,” Jessica Jensen, executive vice president, Clinical Development of POINT Biopharma, stated in a press release. “We are grateful for patients who agreed to be screened for this study, the trial investigators and their hard-working staff, our research partners, and the POINT team for their passion and commitment to the program.”

The open-label SPLASH trial (NCT04647526) specifically enrolled patients whose tumors express PSMA; who have experienced disease progression on an androgen receptor–axis-targeted therapy (abiraterone acetate [Zytiga], enzalutamide [Xtandi], darolutamide [Nubeqa], or apalutamide [Erleada]) in either the castration-sensitive or CRPC setting; and who are not eligible for or decline chemotherapy. Patients must have an ECOG performance status of 0 to 1 and a positive PSMA-PET scan on a validated test, such as 68Ga-PSMA-11 or 18F-DCFPyL (piflufolastat F 18; Pylarify).

The randomization phase of the study assigned patients in a 2:1 ratio to either PNT2002 (arm A) or abiraterone or enzalutamide (arm B).

 Crossover from the control arm to receive PNT2002 will be allowed at radiographic progression among patients who meet the study protocol eligibility criteria. The primary end point of the study is radiographic progression-free survival (rPFS). Other key end points include overall response rate, overall survival, biochemical PFS, duration of response, pharmacokinetics, and safety.

The estimated primary completion date for the randomization phase is March 2023; however, data from the lead-in phase will be made available prior to that time. Overall, patients will continue to be followed for up to 5 years following their first treatment dose.

Based on a strategic collaboration that POINT entered into with Lantheus Holdings, POINT is funding the SPLASH trial and Lantheus, in collaboration with POINT, will be responsible for filing a New Drug Application with the FDA should it be warranted by the SPLASH results.

1. POINT Biopharma Completes Randomization in PNT2002’s Phase 3 SPLASH Trial. Published online and accessed January 12, 2023. https://yhoo.it/3ZxaHNx.

2. United States National Institutes of Health National Library of Medicine. ClinicalTrials.gov. Study Evaluating mCRPC Treatment Using PSMA [Lu-177]-PNT2002 Therapy After Second-line Hormonal Treatment (SPLASH). Site last updated July 29, 2021. Accessed August 11, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04647526.

Enrollment complete in phase 3 mCRPC trial of novel PSMA-targeted agent

At the 2023 SUO Annual Meeting, Grant Stewart, MD, PhD, discussed the potential of neoadjuvant therapy as a tool to help optimize the management of patients with localized kidney cancer.

Stewart began his presentation with a recap of recent notable completed trials of neoadjuvant therapy in renal cell carcinoma (RCC).

He started with a single-arm, single institution phase 2 trial of neoadjuvant axitinib (Inlyta), an oral TKI, in patients with locally advanced, nonmetastatic clear cell RCC.

 Following single-agent axitinib therapy, patients in the trial underwent partial or radical nephrectomy.Among 24 treated patients, the median reduction of primary renal tumor diameter was 28.3%. Almost half (46%) of patients had a partial response (RECIST) and 13 patients had stable disease.

These data helped inform the launch of the phase 2 NAXIVA trial, a single-arm, multi-center trial that included 20 patients with RCC with venous tumor thrombus.

 Patients were treated with neoadjuvant axitinib for up to 8 weeks prior to radical nephrectomy. Overall, 35% of patients (n = 7) had a response and 7 (41.2%) of 17 patients who underwent nephrectomy had less invasive surgery than originally planned.

Despite these promising outcomes, Stewart said the single-agent TKI approach used in NAXIVA is outdated and the trial had other shortcomings, such as being a single-arm trial with no overall survival end point.

The next approach explored by researchers was neoadjuvant immune checkpoint inhibition, starting with single-agent therapy, explained Stewart; however, he said that in 2 trials of neoadjuvant nivolumab (Opdivo), “none of the patients had a partial response.”

Moving on, researchers next explored the potential of combining a TKI with immunotherapy. For example, the NeoAvAx trial explored the combination of the PD-L1 inhibitor avelumab (Bavencio) and axitinib (Inlyta) in patients with high-risk, non-metastatic clear-cell RCC.

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 (83%) of 12 were disease-free at the study data cutoff. At a median follow-up of 23.5 months, the median overall survival and median disease-free survival had not yet been reached. No patients had progression of their primary tumor.

Stewart said these results are promising but since the response rate was higher at 46% in one of the previous trials of single-agent axitinib, it will now be important to determine if the immunotherapy component of this regimen adds a benefit. For his part, Stewart said he thinks the immunotherapy is having a high impact and looks forward to additional data.

Stewart also mentioned the phase 3 PROSPER trial, which compared perioperative nivolumab with observation in patients with high-risk, localized RCC scheduled to undergo nephrectomy. The study found that the perioperative approach of administering nivolumab before and after surgery did not improve recurrence-free survival, which was similar between the nivolumab and observation arms (HR, 0.97; 95% CI, 0.74-1.28; 

“Unfortunately the trial was negative, but we are going to learn a lot from this study from the translational data in terms of what single-agent immunotherapy is doing in this setting,” said Stewart.

Looking ahead, Stewart said there are 11 ongoing neoadjuvant RCC clinical trials listed on ClinicalTrials.gov, comprised of 1 phase 1 trial and 10 phase 2 trials. Of note, only 2 of the studies are randomized and none of the trials have survival end points.

Stewart suggested that an adaptive clinical trial design, similar to the one employed in the I-SPY 2 neoadjuvant breast cancer trial, can help shift the research away from single-agent studies and “better identify the agents we should be using in kidney cancer.”

He concluded by describing how he is currently using this approach in the ongoing WIRE trial at Cambridge University Hospitals in the United Kingdom. A description of this trial published in 

“WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritizing promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda.”

1. Stewart G. Neoadjuvant Therapy in RCC: Lessons From RCC and Beyond. Presented at: 2022 SUO Annual Meeting. November 30 – December 2, 2022; San Diego, CA.

2. Karam JA, Devine CE, Urbauer DL, et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. 

. 2014;66(5):874-80. doi: 10.1016/j.eururo.2014.01.035

3. Stewart GD, Welsh SJ, Ursprung S, et al. A Phase II study of neoadjuvant axitinib for reducing the extent of venous tumour thrombus in clear cell renal cell cancer with venous invasion (NAXIVA). 

. 2022 Oct;127(6):1051-1060. doi: 10.1038/s41416-022-01883-7

4. 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

5. M. Allaf, S.E. Kim, L.C. Harshman, et al. LBA67 - Phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients (Pts) with renal cell carcinoma (RCC) undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089.

6. Ursprung S, Mossop H, Gallagher FA, et al. The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol. 

. 2021;21(1):1238. doi: 10.1186/s12885-021-08965-4

Jason M. Broderick

Articles

Darolutamide nears EU approval for mHSPC

Pembrolizumab plus enzalutamide/ADT falls short in mHSPC

Enrollment complete in phase 3 mCRPC trial of novel PSMA-targeted agent

Is neoadjuvant therapy a pathway to improved outcomes in localized kidney cancer?