Will Pizii

Extended darolutamide (Nubeqa) safety and tolerability results indicate that patients with metastatic castration-resistant prostate cancer who were treated with the drug for more than 4 years tolerated well its adverse events (AEs).

The data were reported at the 2022 American Urological Association Annual Meeting in New Orleans by Robert Hugh Jones, MD, PhD, from Cardiff University and Velindre Cancer Centre in Cardiff, Wales.

Thirty patients were enrolled in the 2-part, multicenter, international, phase 1 ARAFOR study (NCT01784757),

 which was investigating the pharmacokinetics of the next-generation androgen receptor inhibitor in a 3-period crossover study with an open-label extension arm for long-term safety and tolerability assessment. Six patients in the trial received darolutamide treatment for over 4 years. The median duration of treatment for these 6 patients was 63 months (range, 49-90), and 1 patient completed the study and entered a darolutamide rollover study (NCT04464226).

All 6 patients reported any-grade treatment-emergent AEs (TEAEs), and 5 patients reported grade 3 TEAEs. However, no grade 3 TEAEs were reported in more than 1 patient at a time, and investigators deemed these grade 3 TEAEs to be unrelated to darolutamide treatment. Grade 3 AEs included 1 event each of nausea, hepatic cirrhosis, pyelonephritis, accident, femoral neck fracture, spinal compression fracture, paraneoplastic syndrome, hematuria, lung disorder, and pulmonary embolism.

Four patients experienced serious TEAEs. The study authors noted that no serious TEAEs were reported in more than 1 patient at time, and none of these TEAEs were related to darolutamide treatment. No TEAEs led to drug discontinuation. The only drug-related AEs of fatigue, solar dermatitis, and tinnitus were reported in 2 patients at a grade 1 severity.

The most common AEs reported in 2 or more patients were grade 1 solar dermatitis, rib fracture, and dysuria; grade 2 diarrhea, abdominal pain, and arthralgia; and grade 3 nausea and hematuria.

All patients received endocrine therapy before darolutamide treatment, and none received chemotherapy prior to the start of the study. Five patients had prior or concomitant treatment with bicalutamide (Casodex), 4 received triptorelin acetate, 1 had goserelin (Zoladex) or goserelin acetate, and 1 had leuprorelin acetate (Lupron).

The median age of patients was 69 years (range, 58-73). All 6 patients were White, with 3 hailing from France, 2 from Latvia, and 1 from Finland. Five patients had normal renal function, and 1 patient had a mild impairment. Three patients had normal hepatic function, and the rest had a mild impairment. The baseline ECOG performance status saw 5 patients scoring 0 and 1 patient scored a 1. Two patients had a Gleason score less than 7, and the other 4 scored 7 or higher.

Patients’ median time since initial diagnosis was 63.8 months (range, 17.9-133.6). Patients were initially treated with chemical castration (n = 2), radiotherapy (n = 3), and prostatectomy (n = 1) before entering the study. The median baseline prostate-specific antigen level was 9.25 μg/L (range, 4.6-22.6).

Investigators found with these long-term treatment data that the safety and tolerability of darolutamide in patients with mCRPC was favorable and consistent with previous study findings, such as the phase 3 ARAMIS (NCT02200614) and ARASENS (NCT02799602) trials.

1. Jones, RH. Long-term safety of darolutamide among patients with metastatic castration-resistant prostate cancer who received more than 4 years of therapy. Poster presented at: 2022 American Urological Association Meeting; May 12-May 16, 2022; New Orleans, LA. Accessed May 14, 2022. https://university.auanet.org/aua2022/posters/2044084.pdf

2. Shore ND, Tammela TL, Massard C, et al. Safety and antitumour activity of ODM-201 (BAY-1841788) in chemotherapy-naïve and CYP17 inhibitor-naïve patients: follow-up from the ARADES and ARAFOR Trials. 

 2018;4(4):547-553. doi:10.1016/j.euf.2017.01.015

3. Study to continue treatment with darolutamide in patients who have been participating in previous darolutamide studies supported by Bayer. ClinicalTrials.gov. Updated May 12, 2022. Accessed May 14, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04464226?term=NCT04464226&draw=2&rank=1

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No grade 3 TEAEs were reported in more than 1 patient at a time, and investigators deemed these grade 3 TEAEs to be unrelated to darolutamide treatment.

Darolutamide is well tolerated in patients with mCRPC over long term

The final overall survival (OS) analysis from the ARCHES trial published in the 

 showed that adding enzalutamide (Xtandi) to androgen deprivation therapy (ADT) significantly improved overall survival in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

The final results from the phase 3 study showed that the addition of enzalutamide to ADT reduced the risk of death by 34% versus placebo plus ADT (median not reached in either group; hazard ratio [HR], 0.66; 95% CI, 0.53-0.81; 

 <.001). These data back the efficacy trend demonstrated in the primary analysis, which showed that adding enzalutamide to ADT significantly improved radiologic progression-free survival (rPFS).

Investigators in the phase 3 ARCHES trial (NCT02677896) enrolled 1150 patients with mHSPC and randomized them 1:1 to receive 160 mg of enzalutamide once daily plus ADT or to receive placebo plus ADT. Patients were stratified by disease volume and prior docetaxel (Taxotere) use. After the preliminary analysis, the study was unblinded to allow those who were randomly assigned to the placebo group to cross over to the enzalutamide group in an open-label extension. Key secondary end points reported in this updated analysis are overall survival (OS), defined time from random assignment to death from any cause, and rPFS.

Investigators reported 154 deaths among the 574 patients who were randomly assigned to enzalutamide plus ADT compared with 202 deaths of the 576 patients who were randomly assigned to placebo plus ADT.

After ARCHES unblinded, 184 patients (31.9%) in the placebo plus ADT arm remained progression-free and consented to cross over. Among those who crossed over, 180 of these patients (31.3%) received treatment with enzalutamide plus ADT, with a median time to crossover of 21.5 months. After 356 deaths, the data cutoff for the final OS analysis with a median follow-up time of 44.6 months.

After treatment discontinuation, 131 patients (23%) in the enzalutamide plus ADT group and 221 patients (38%) in the to placebo plus ADT group received subsequent life-prolonging therapy. Including patients who crossed over, 401 patients (70%) randomly assigned to placebo plus ADT received subsequent life-prolonging therapy.

The enzalutamide plus ADT group experienced a delayed time to first subsequent antineoplastic therapy of which the median was not reached vs 40.5 months for placebo plus ADT (HR, 0.38; 95% CI, 0.31-0.48). The treatment of enzalutamide plus ADT reduced the risk of radiographic progression or death by 37%, extending the median rPFS by approximately 11 months compared with treatment with placebo plus ADT. Prostate specific antigen progression was found in117 patients (20%) in the enzalutamide plus ADT group compared with 259 (45%) in the placebo plus ADT group.

The median age of patients in the enzalutamide group was 70.0 years (range, 46-92), 70.0 years (range, 42-92) in the placebo group, and 69.0 years (range, 51-89) in those who crossed over from the placebo group. More than 75% of all patients were white. Patients had ECOG performance scores of either 0 or 1, with patients in the enzalutamide group, placebo group, and crossover group scoring 0 in 78.0%, 76.9%, and 84.2%, respectively. Visceral disease was observed in 11% of patients in both enzalutamide and placebo groups as well as 9.4% of patients in the crossover group. A small portion of patients received no previous ADT (6.8% in the enzalutamide group; 10.6% in the placebo group; 11.4% in the crossover group).

The median treatment duration was 40.2 months for the enzalutamide group, 13.8 months for the placebo group, and 23.9 months in the crossover group. Investigators noted the occurrence of treatment-emergent adverse events was consistent with the primary analysis, and no new safety signals were identified.

Previously reported efficacy benefits with enzalutamide plus ADT vs placebo plus ADT remain and are further confirmed with additional follow up. Along with no new emerging safety signals, these data indicate that longer-term use of enzalutamide was well tolerated and not associated with any new toxicity concerns.

1. Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer [published online ahead of print April 14, 2022]. 

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The final results from the phase 3 ARCHES trial showed that the addition of enzalutamide to androgen deprivation therapy also continued to improve radiologic progression-free survival and other secondary end points.

Final survival analysis shows significant boost with enzalutamide in mHSPC

Researchers hoping to improve outcomes in patients with locally advanced renal cell carcinoma (RCC) are increasingly focusing on the adjuvant and neoadjuvant settings.

For example, adjuvant pembrolizumab (Keytruda) was recently approved for the treatment of patients with RCC at intermediate or high risk of recurrence following nephrectomy,

 and further research is looking to bringing this approach to therapy—not just with immunotherapy but also with targeted therapy—into practice ahead of nephrectomy to further prevent the risk of recurrence.

One such trial is the global phase 3 PROSPER RCC trial (NCT03055013) looking at neoadjuvant and adjuvant nivolumab (Opdivo) in patients with high-risk RCC scheduled for radical or partial nephrectomy. Naomi B. Haas, MD, is the medical oncology study monitor for the trial and expects this will have a significant impact on the future role of neoadjuvant and adjuvant immunotherapy for patients with RCC.

In an interview during the 2021 International Kidney Cancer Symposium, Haas, the director of the Prostate and Kidney Cancer Program and professor of medicine at the Hospital of the University of Pennsylvania, discussed the potential of the neoadjuvant approach in treating patients with RCC as well as ongoing research in this setting.

Can you discuss what has been the success of the neoadjuvant targeted/immunotherapy strategy in the treatment of patients with RCC?

A number of VEGF TKI [tyrosine kinase inhibitor] approaches have been taken in the neoadjuvant setting. The general approach has been, given that cabozantinib [Cabometyx] is one of the VEGF TKIs, that it is thought to be one of the most active in RCC. [With this approach], the idea has been if it can be administered in a safe way and achieve as much tumor shrinkage as possible. One of the challenges with VEGFR TKIs, in general in the neoadjuvant setting, has been that they interfere with wound healing to some extent. Cabozantinib has a half-life of about 5 days, so the timing of it has to be such that it can be administered, and then I allow enough time to stop [treatment] where the patient can safely proceed with surgery but also not be off the drug so much that a rebound effect [occurs]. And I think we’ve seen with other trials that that is indeed possible.

The neoadjuvant approach has been an important approach for the immune checkpoint inhibitors. People [previously] have made comments without any data, only based on personal experience [about immune checkpoint inhibitors’ efficacy]. Several years ago, somebody stood up at a meeting and made the comment that there might be more scarring seen with immune checkpoint inhibitor therapy before surgery, and that makes surgery difficult. There have been a couple of neoadjuvant phase 2 trials that have been conducted that have shown that it is a safe approach and it hasn’t made surgery impossible in these patients, because immune checkpoint inhibitor therapy doesn’t interfere with wound healing, and I think the concerns about things like pneumonitis and intubating a patient have not borne out, that increasingly people are feeling a little bit better about offering that as a neoadjuvant approach.

What were the important points made by the panelists during the session regarding neoadjuvant therapy?

One of the very valuable things that neoadjuvant therapy does is it allows people to understand the biology of the tumors and who is benefiting and who isn’t benefiting from these approaches by doing some of the valuable correlative and molecular work that is needed. I think that one of the other take-home messages is that there’s still a relative lack of consensus, so we do need to wait for some of the bigger trials. For example, the PROSPER trial is trying to address both the feasibility, the safety, and also the signal that is achieved by offering neoadjuvant therapy to patients. I think one of the other [important] messages is that we need to figure out how to address these kinds of trials so they’re available to everybody and not just at tertiary cancer centers.

What are the key challenges with designing neoadjuvant trials in this disease?

One of them is good coordination between the urology and the medical oncology teams. Usually, the urologist is the first person to see the patients. So urologists have to be aware of neoadjuvant approaches and have to be willing to have that conversation with patients ahead of time to alert them to clinical trials. It’s not the standard of care right now to offer neoadjuvant [treatment] for RCC, but certainly, there’s a lot of surgical experience in urothelial malignancies and also in other disease sites, such as colorectal cancer and breast cancer, where it is common. One of the impediments is the urologist bringing it up to the patients. The second is being able to coordinate care because generally these drugs are administered by a medical oncologist. So [it is the] speed in getting patients [to treatment that is key] and having a multidisciplinary approach. The other [challenge] is making a trial simple enough for the medical oncologist, the urologist, and the patient to all feel that it’s easily accomplished and easy to enroll.

What are your expectations for neoadjuvant trial design going forward?

I think it’s not going to go away. I think that neoadjuvant therapy trials can also help to understand, in addition to who benefits from any kind of perioperative treatment, whether it’s adjuvant or neoadjuvant based on the correlatives, but I also think that people are getting more comfortable with this approach. It was a real learning experience several years ago when the PROSPER trial launched, but I think a lot of urologists now have a comfort level that they didn’t have before. I think that one of the other values is understanding the duration of either the neoadjuvant or the adjuvant approaches.

Since then, lenvatinib (Lenvima) has become such an important drug in the RCC space, and there are ongoing trials in the neoadjuvant setting and for other diseases like thyroid cancer and hepatocellular carcinoma. Do you think we’re close to having a study of neoadjuvant lenvatinib in RCC?

We’re about to launch a lenvatinib plus pembrolizumab trial at the University of Pennsylvania. I also heard Dr [Viraj] Master also talk about [a trial] at Emory [University] [NCT04393350]. There are phase 2 initiatives that are being done to understand the benefit in patients. Lenvatinib is an interesting drug because it probably has some immunologic aspects that can augment its activity with immune checkpoint inhibitors. There [are] some data to suggest that it might help stimulate Tregs [regulatory T cells] and it might be a way to prevent T-cell exhaustion, which are 2 reasons that immune checkpoint inhibitors sometimes don’t work in patients. I think it’s a very useful approach, and so I feel encouraged about that.

1. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed December 9, 2021. https://bit.ly/3rNXC3R

Naomi B. Haas, MD, discusses efforts to improve care in locally advanced renal cell carcinoma through research in the neoadjuvant setting. 

Will Pizii

Articles

Darolutamide is well tolerated in patients with mCRPC over long term

Final survival analysis shows significant boost with enzalutamide in mHSPC

Researchers look to neoadjuvant setting to advance RCC paradigm