Comparing Nab-Paclitaxel and Paclitaxel in Platinum-Refractory Bladder Cancer - Srikala Sridhar
November 4, 2020
Investigator-initiated trials (IITs) often tackle important questions that are not addressed elsewhere. [transcript] Compared with a pharmaceutical company–managed trials, benefits of IITs include generating data in a real-world setting and resolving issues that confound physicians in daily practice. A recent open-label, phase 2 randomized IIT was led by the Canadian Cancer Trials Group (CCTG), based at Queen’s University in Kingston, Ontario with collaboration by the Australian and New Zealand Cancer Trials Group Limited (ANZUP). It compared the efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel* and paclitaxel in patients with platinum-refractory metastatic urothelial cancer.
Nab-paclitaxel was designed to improve the therapeutic index, and it doesn’t require steroid premedication. In 2013, a single-arm study by Y-J Ko and SS Sridhar, et al out of Sunnybrook Odette Cancer Centre in Toronto, Ontario showed that nab-paclitaxel was well tolerated in 48 patients with pretreated, advanced urothelial cancer, and the tumor response was encouraging. Those results prompted the CCTG/ANZUP IIT.
While the primary endpoint was not met—nab-paclitaxel did not prolong progression-free survival compared with paclitaxel—another interesting result, likely related to advances in supportive care measures [transcript], ensued. Also of interest is unexpected information pertinent to the dosing strategy.
Enjoy this video as Dr. Alicia Morgans, Associate Professor of Medicine and GU Medical Oncologist at Northwestern University, Chicago, Illinois, USA, interviews Dr. Srikala S Sridhar, Associate Professor of Medicine at the University of Toronto and Clinician Investigator at University Health Network–Princess Margaret Cancer Centre, Toronto. Official study title: A multicentre randomized phase II trial comparing nab-paclitaxel to paclitaxel in patients with advanced urothelial cancer progressing on or after a platinum-containing regimen. [https://clinicaltrials.gov/ct2/show/NCT02033993]
*Nab-paclitaxel is FDA-approved in metastatic breast cancer, locally advanced or metastatic non-small cell lung cancer (NSCLC), and metastatic adenocarcinoma of the pancreas. [Abraxane PI 2018] Paclitaxel is FDA-approved in advanced ovarian cancer, breast cancer, NSCLC, and AIDS-related Kaposi’s sarcoma. [Pacitaxel PI 2018] There is, of course, a long list of non-FDA-approved indications for paclitaxel, including for metastatic or advanced bladder cancer in combination therapy with gemcitabine. [Farrar 2020; NCI 2020]
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5. Paclitaxel Injection, USP. Prescribing Information. May 2018. Hospira, Inc, Lake Forest, Illinois, USA.
6. National Cancer Institute. Bladder Cancer Treatment (PDQ®)–Health Professional Version. September 2020. Accessed October 22, 2020 at https://www.cancer.gov/types/bladder/hp/bladder-treatment-pdq
7. Sridhar SS, Blais N, Tran B, et al. Efficacy and safety of nab-paclitaxel vs paclitaxel on survival in patients with platinum-refractory metastatic urothelial cancer. The Canadian Cancer Trials Group BL.12 randomized clinical trial. JAMA Oncol. 2020 Sep 17;e203927. doi: 10.1001/jamaoncol.2020.3927. Online ahead of print.
Srikala Sridhar MD, MSc, FRCPC is an Associate Professor within the Department of Medicine, Division of Medical Oncology at the University of Toronto. She is head of the genitourinary cancers medical oncology site group at the Princess Margaret Hospital and treats primarily bladder, prostate, and kidney cancers. She has an active research program in the area of bladder cancer, evaluating new therapies and imaging modalities; and is currently the international study chair of a National Cancer Institute of Canada (NCIC) phase 2 clinical trial. In 2011, she was recognized for her teaching excellence with a University of Toronto teaching award.
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Efficacy and Safety of nab-Paclitaxel vs Paclitaxel on Survival in Patients With Platinum-Refractory Metastatic Urothelial Cancer
Cctg BL12: Randomized Phase II Trial Comparing Nab-Paclitaxel to Paclitaxel in Patients with Advanced Urothelial Cancer Progressing On or After a Platinum Containing Regimen
Alicia Morgans: Hi. My name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago, Illinois in the United States. I'm so excited to have here with me today, a friend and colleague, Dr. Kala Sridhar, who is an associate professor of medicine at the University of Toronto and who is at the Princess Margaret Cancer Center. Thank you so much for being here with me today, Dr. Sridhar.
Srikala Sridhar: Thanks for having me, Alicia.
Alicia Morgans: Wonderful. So I'd like to talk with you about a really interesting study that you and the Canadian Cancer Trials Group performed that was recently published in JAMA Oncology. First, congratulations for such a wonderful publication. And second, can you tell us a little bit about this trial, which looked at nab-paclitaxel versus paclitaxel in patients with metastatic urothelial cancer?
Srikala Sridhar: Yeah, absolutely. Thanks for having me and talking about this paper that was recently published on this study. So basically, this was an investigator-initiated, Canadian Clinical Trials Group, as you mentioned, that led the study with collaboration from ANZUP. So that's the Australia and New Zealand group. And this was a randomized phase two study comparing paclitaxel against nab-paclitaxel in platinum-refractory metastatic urothelial carcinoma. And this was really based on a prior single-arm study that showed encouraging activity of the drug nab-paclitaxel. And nab-paclitaxel is a drug that has been used previously in breast cancer, and it was felt that the formulation, being albumin encapsulated nanoparticle, maybe not only better tolerated, but potentially more effective. So based on the single-arm study where we did show encouraging activity, we embarked on this randomized trial.
Alicia Morgans: Well, great. Well, what did you ultimately find when you compared these two forms of paclitaxel, paclitaxel, and nab-paclitaxel?
Srikala Sridhar: Sure. So this study was open from January 2014 to 2017, which is important to remember because it predates where we are today with the immunotherapy targeted therapy and antibody-drug conjugates. So in total, we accrued 199 patients, about 30% had liver metastasis. And at around 16.4 months of follow-up, we found that, in terms of the progression-free survival, which was a primary endpoint, that there was really no significant difference. So 3.4 months versus three months. So that's an important point to keep in mind, that nab-paclitaxel was not superior to paclitaxel, in terms of PFS, which as I mentioned is a primary endpoint. And then in terms of median overall survival, 7.5 versus 8.8 months. So again, really close. But I think what was really interesting to me was when we look at the objective response rates; it was 22% for nab-paclitaxel, but it was actually 25% for paclitaxel. And this is higher than was ever shown before for the taxane. And if you remember, starting to get close to the numbers we're seeing for some of the immunotherapies in the platinum-refractory setting, which are all in that same ballpark.
Alicia Morgans: Yeah. So I agree. And I think that was really such an interesting point to make, that this seems to have a better response rate, a better effect, than we may think about paclitaxel from those previous studies. And I wonder if you think that this is actually generalizable to other practices, maybe practices that are not participating in a clinical trial. Do you think that this was unique to certain centers in Canada and in Australia and New Zealand or do you think, because there were so many centers involved, that this may actually reflect our better supportive processes maybe or just adherence to continuing to try the treatment and not giving up too soon?
Srikala Sridhar: Yeah, I think I would sort of say maybe all of the above, in particular, the latter. So I think with sort of 199 patients on the study, and if we look at them together, both arms were showing upwards of 20% response, 22 and 25%. So I believe that it is truly at that level. I think we have made significant advances with our supportive care treatments. And that's what I tell patients sometimes, that even if we haven't made major advances, we're starting to. Of course, in this disease, the biggest advance as we've seen is really in the supportive care therapy. So, I think that has potentially helped us to achieve better response rates with these drugs.
And third, I think, as you say, at the time when this study was happening, we really didn't have much else. And so I think there was a bit of a commitment to sticking with it, staying with it, and you did see patients derive benefit. I had some very long-term responders; it was fairly well tolerated. I think the only thing I'll say, in practice now, what I find and what is different than what was happening on the trial, on the trial we tested it once every three-week dosing, which is similar to what we had done in the single-arm phase two. But I think in practice, given these patients can be older, frailer at times, I tend to use a weekly dosing. So two weeks on, one week off; I find it's well-tolerated and we get some good benefits. And it's sort of my go-to treatment when I don't have clinical trials, I don't have anything else.
Alicia Morgans: I agree with you. I think that we all have these patients, whether we have access to some of the novel agents or not, there are patients who will get through everything that we have at our disposal and not be eligible for clinical trials, but need something else. So I think it's wonderful for us to not forget about potential treatments that may have been actually developed many years ago, particularly since we don't necessarily know how these treatments are going to act in our new system with better supportive care. And this study actually really, I think, clarifies for us how we can use, in at least one way, not the weekly method at least, but at least one way an old reliable therapy and remind us that this is an option. And I have a question too about this. So I have used paclitaxel actually pretty regularly in these settings, particularly when we didn't have things like immunotherapy or afatinib or [inaudible], et cetera. But there are definitely folks who prefer docetaxel. Do you have a preference between the two drugs?
Srikala Sridhar: I mean, I know. It's curious, right? So I tend to prefer paclitaxel, and part of it is just, that's what I've always done. I'd sort of done docetaxel for prostate and paclitaxel for urothelial, and it just sort of evolved that way. I know how to dose it, and it might even be the fact that I can go to a weekly regimen easily and it's familiar to me. So, that's why I tend to use it. It is off-patent, it's inexpensive. And I think when we think about around the world, and I think I brought this up at the ESMO discussion as well, that as we wait for all these wonderful new drugs to be approved and available, which may take sometimes up to 18 months to two years, depending on where you are, I think having a drug like this, with documented activity, is really important.
Alicia Morgans: I completely agree. And I think it's nice too, that you have the head-to-head against this other formulation of paclitaxel so that we understand to the toxicity. And I really commend the groups, the Canadian Cancer Trials Group, and ANZUP, for taking the time to do this and then really putting it together in a publication that is so meaningful to our community and not forgetting that these options are important to us also. So as we think through this great paper and the work that all of you have done for the last number of years, what is your concluding message to folks who are listening?
Srikala Sridhar: I think my message is don't forget the old, relatively inexpensive, yet effective drug paclitaxel in metastatic urothelial carcinoma. I think, as well, it's good to think about things like quality of life. I know you and I have talked about this before, but if you can get a drug that works and is reasonably well tolerated, I think that's important, and I think that's a second thing. And third, I think we need to keep doing investigator-initiated academic trials like this, asking important questions that sometimes aren't asked in other venues, and I think that would be the third point I would make.
Alicia Morgans: Great. Well, thank you for this and thank you for going through it with all of us. I really appreciate your time and expertise.
Srikala Sridhar: Thanks, Alicia. Thanks for having me and take care.