Enzalutamide With Gemcitabine and Cisplatin Safely Targets AR+ Metastatic Bladder Cancer

In an interview with <em>Targeted Oncology</em>, Shilpa Gupta, MD, discussed the results of the phase I/Ib trial of enzalutamide and gemcitabine and cisplatin in&nbsp;metastatic bladder cancer and defining platinum ineligibility in patients with metastatic urothelial cancer.

Shilpa Gupta, MD

Targeting androgen-receptor (AR) signaling in metastatic bladder cancer with enzalutamide (Xtandi) in combination with gemcitabine and cisplatin is considered a safe and tolerable regimen, based on the results of a phase I/Ib trial.1

The dose-escalation phase included patients with AR-positive and AR-negative disease and followed the 3+3 design. The 2 cohorts were treated with enzalutamide, either 80 mg or 160 mg and the standard dosage of gemcitabine. Then, in the dose-expansion phase, 12 patients with stage IV AR-positive BC were treated with the proper dose of enzalutamide discovered in the previous phase (160 mg). These dosages were continued for up to 6 cycles. Enzalutamide was then given as maintenance therapy until disease progression.

The results from the trial found enzalutamide plus gemcitabine and cisplatin to be safe and the toxicities were tolerable, meeting the 2 primary endpoints of the study. Additionally, the median progression-free survival was 7.68 months and the median overall survival was 10.59 months. Of the 8 evaluable patients, 1 achieved a complete response and 4 had stable disease.

In an interview withTargeted Oncology, Shilpa Gupta, MD, associate professor of medicine, University of Minnesota, discussed the results of the phase I/Ib trial of enzalutamide and gemcitabine and cisplatin in metastatic bladder cancer and defining platinum ineligibility in patients with metastatic urothelial cancer (mUC).

TARGETED ONCOLOGY: Can you provide background on the phase I/Ib trial of enzalutamide with gemcitabine and cisplatin in metastatic bladder cancer?

Gupta: We know that immunotherapy has changed the treatment paradigm for bladder cancer, but targeted therapies have a lot of scope we need to explore and AR is a pathway that is upregulated in bladder cancer and we did the first trial looking at AR inhibitor enzalutamide in combination with gemcitabine and cisplatin as first-line therapy in metastatic bladder cancer.

TARGETED ONCOLOGY: What were the findings of this study?

Gupta: This was a phase I/Ib dose-finding study and we wanted to see if the combination is safe. And in the dose-finding portion, we found that standard dose of enzalutamide 160 mg a day was safely administered with gemcitabine and cisplatin in standard doses. Then we expanded the study to only patients with AR-positive bladder cancer.

It was a small phase I study but we saw that out of 10 patients, a majority of patients had evidence of clinical activity. One patient who had complete response was a female patient with over 90% expression of AR. To date, she's in complete remission 3 years post treatment and several patients had partial responses and stable disease.

AR is a target worth exploring such good novel anti-androgen agents available to us and combination with immunotherapy is something that we plan to do moving forward.

The combination was very safe. Most of the [adverse effects] we saw were from chemotherapy. There were no addition toxicities with the addition of enzalutamide.

TARGETED ONCOLOGY:What is the biggest challenge you are hoping to address with this potential combination regimen?

Gupta: We want to have more targeted therapies on board because immunotherapy as a single agent only results in around a 20% response rate in bladder cancer. Designing studies that have agents that are not too toxic and can be safely combined with immunotherapy and/or chemotherapy is what we need to do moving forward.

I see a lot of promise with anti-androgen therapies because they're relatively well tolerated and we have extensive experience from prostate cancer. This study provides some direction that it can be safely given in bladder cancer too.

TARGETED ONCOLOGY:Are there drugs you can potentially combine with enzalutamide in the space?

Gupta: We are seeing that enzalutamide also has immune modulatory activities when combined with pembrolizumab (Keytruda) in prostate cancer. That certainly sets the field for combining it with immunotherapy in bladder cancer also. Because AR is so widely upregulated in bladder cancer, it's certainly a therapy we need to explore.

We're actually doing a companion preclinical study on those lines to look at the molecular efficacy of enzalutamide in ex vivo organ cultures of bladder cancer cells, so we know if it is active at the molecular level.

TARGETED ONCOLOGY: Can you explain the background to your research looking into patients with &ldquo;platinum-ineligible&rdquo; mUC?2

Gupta: The majority of patients with bladder cancer are not eligible to receive cisplatin-based chemotherapy due to comorbidities like hearing loss, renal dysfunction, or poor performance status. These criteria [for cisplatin ineligibility] were well defined by Matt Galsky a few years ago. More recently, atezolizumab (Tecentriq) and pembrolizumab were approved for patients who are not eligible to receive cisplatin.

However, last year, the FDA came back with an alert stating that only patients whose tumors express high levels of PD-L1 or patients who are not able to receive carboplatin can get single-agent immunotherapy. That's putting a lot of limitations on the use of pembrolizumab and atezolizumab. But the truth is that no one knows [which] patients can't even get carboplatin. So, we wanted to answer this question to come up with a uniform consensus for defining eligibility for clinical trials and providing some guidance at point of care.

We developed this online tool and we sent it to around 56 genitourinary oncologists practicing in bladder cancer [along] with a list of criteria like performance status, age, renal creatinine clearance, hearing loss, neuropathy, etc. Over 80% of the [physicians] came back with their responses and had the option to add other factors. Then we fine-tuned the survey and sent round 2. Based on that, we came up with a consensus that age is not a criterion for patients cannot be given platinum or carboplatin and a creatinine clearance of less 30 milliliters per minute is the group of patients that physicians would not feel comfortable giving carboplatin to. [Also], neuropathy grade ≥3 and equal performance status of grade ≥3. These 4 criteria define a patient to be platinum ineligible.

Once we know the results from the ongoing trials, we'll know more about how this evolves. This is a good step in the direction toward trying to define the subset of patients and provide guidance to oncologists about when to use immunotherapy.

TARGETED ONCOLOGY: Is there any other research you find particularly hopeful for treatment ofmetastatic bladder cancer?

Gupta: [The abstracts I found hopeful] at the ASCO meeting in bladder cancer were the maintenance trial of pembrolizumab in metastatic bladder cancer, which I collaborated on with Matt Galsky. This is the first time that we've looked at the switch maintenance strategy of immunotherapy in patients who have at least stable disease following first-line platinum-based chemotherapy and we'll know whether moving immunotherapy early on confers an advantage or not.

The second trial we're looking forward to is [Jonathan E. Rosenberg’s] CALGB 90601 trial where he tested whether the addition of VEGF antibody bevacizumab [Avastin] to gemcitabine and cisplatin compared to gemcitabine and cisplatin alone is better. We were excited to see what the data showed.

TARGETED ONCOLOGY: What do we need to do going forward to determine which patients are most optimal to receive immunotherapy?

Gupta: Immunotherapy has changed the way we treat bladder. We didn't have any therapies for the past 40 years. However, we only see responses in about 20% to 25% of patients. We need to do a much better job at identifying patients who will not respond to immunotherapy and spare them the treatment and the risk of having disease progression and also financial toxicity.

Biomarkers are definitely an unmet need, but we don't have a clear sense of which is a good biomarker. PD-L1 status has not panned out to be a biomarker by itself and tumor mutational burden needs to be validated further. [I believe that], we need to tie in multiple biomarkers to come up with a composite sense of which patients may or may not respond to immunotherapy, and we are not there yet.

TARGETED ONCOLOGY: Do believe there will always be a role for platinum-based chemotherapy, or will new regimens eventually replace it?

Gupta: I think we are seeing more and more therapies in the refractory setting. Recently, the FGFR3 inhibitor got approved, which is great. We've seen good data with enfortumab vedotin and other [agents]. The key question of whether chemotherapy will [remain] the backbone for first-line therapy will be answered with the ongoing KEYNOTE-361 and other trials where they're combining platinum-based chemotherapy with immunotherapy and comparing it against chemotherapy alone and immunotherapy alone. Those trials are going to provide us the much-needed answers.


  1. Gupta S, Dhillon J, Magliocco AM, et al. Results from a phase I/Ib trial of enzalutamide and gemcitabine and cisplatin in metastatic bladder cancer (mBC).J Clin Oncol. 2019;37(suppl 7; abstr 471). doi: 10.1200/JCO.2019.37.7_suppl.471.
  2. Gupta S, Sonpavde G, Grivas P, et al. Defining &ldquo;platinum-ineligible&rdquo; patients with metastatic urothelial cancer (mUC).J Clin Oncol.2019;37(suppl 7; abstr 451). doi: 10.1200/JCO.2019.37.7_suppl.451.