Issue: May 25, 2020
Source/Disclosures
Disclosures: Raghavan reports no relevant financial disclosures.
May 26, 2020
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It’s a puzzlement

Issue: May 25, 2020
Source/Disclosures
Disclosures: Raghavan reports no relevant financial disclosures.
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This is the time of year when I often reflect on progress in the area of my greatest clinical interest, genitourinary oncology.

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
Derek Raghavan

The annual parade of GU champions already has occurred at ASCO’s Genitourinary Cancers Symposium, the American Association for Cancer Research Annual Meeting occurs around this time, and the abstracts for the upcoming ASCO Annual Meeting usually are available for review.

This gives me the chance to marvel at the game-changing studies, and at occasional puzzling choices made by some program committees.

‘Treasure trove of riches’

In the domain of prostate cancer, we have a traffic jam that eventually will be sorted out. It is wonderful to have a treasure trove of riches in this space, but who can possibly guess which of the new agents is “best”?

In all likelihood, most of the energy will be expended by specific manufacturers trying to identify small — perhaps important — benefits associated with their patented products.

We know that androgen deprivation therapy has been supplanted by “ADT plus,” and it seems generally that abiraterone and most “-alutamides” add to the impact of ADT, and the impact applies particularly to metastatic disease.

Whereas the hallmark study led by Christopher J. Sweeney, MBBS, of docetaxel plus ADT vs. ADT only applies to bad-risk metastatic prostate cancer, the “-alutamides” clearly work in that space, but also for good-risk metastatic disease.

We must remember that it is still early in the history of “-alutamides.” Time probably will reveal some unexpected late consequences of importance, so we will have to continue to watch this space.

Remember that it took decades to associate ADT with metabolic syndrome, and we are still trying to figure out whether castration improves or reduces male intellect (my wife has an opinion on that!).

It is logical to expect that ADT combination therapy perhaps will alter outcomes in the adjuvant and neoadjuvant settings for men with locally advanced disease, and a bunch of trials finally will resolve that issue.

It’s not a bad thing that the “-oparibs” also offer a useful option for subsets of men with advanced prostate cancer, notwithstanding adding to the traffic jam.

The science of poly(ADP)-ribose polymerase (PARP) inhibition for men with prostate cancer who have mutations of DNA damage repair genes is elegant, and quite well-defined, so it is hardly surprising that many variants of “-oparibs” soon will be in the lexicon. Trials will define the pecking order, and the batting order vis-à-vis use of “-alutamides” and various combinations.

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Immuno-oncology’s role

This year’s offerings whacked immuno-oncology in the domain of advanced prostate cancer, again raising the question of the true utility of sipuleucel-T (Provenge, Dendreon) and equivalent products.

A randomized trial that compared sipuleucel-T plus radium RA-223 dichloride (Xofigo, Bayer) — a known active agent — vs. sipuleucel-T showed improved PSA response, alkaline phosphatase response and time to disease progression with the combination, but no improvement in immune response parameters.

Hmm ... was that a strategic error on the part of the company? I’m not sure I would have highlighted this work, and I imagine that the sponsors were aghast when they heard the news.

The aforementioned C.J. Sweeney also presented a randomized trial that compared atezolizumab (Tecentriq, Genentech) plus enzalutamide (Xtandi; Astellas, Pfizer) vs. enzalutamide for castration-resistant prostate cancer, which also constituted a swing and a miss (respective median survivals were 15.2 months and 16.6 months).

On a happier note, my former colleague Scott T. Tagawa, MD, MS, presented promising data showing the antibody-drug conjugate sacituzumab govitecan (Trodelvy, Immunomedics) — who comes up with these names? — shrinks previously treated bladder cancer, including patients who had already received PD-1 targeted therapy. There were two complete responses among 45 patients, and responses among five of 15 patients with liver metastases — not too shabby, and certainly worthy of further attention.

While we are on the topic of unpronounceable names, let’s not forget the report from Jonathan E. Rosenberg, MD, of enfortumab vedotin (Padcev; Astellas, Seattle Genetics) plus pembrolizumab (Keytruda, Merck).

We all recall a couple of years ago that Daniel P. Petrylak, MD, and colleagues showed activity of enfortumab vedotin — another antibody-drug conjugate that leverages the microtubule-disrupting agent MMAE onto cells expressing nectin-4 — as a single agent in this setting.

Now, Jonathan and his team have added the anti-PD-1 agent pembrolizumab and shown an objective response rate of 73.3%, including a 15% complete response rate. Eight of 16 patients with liver metastases responded to treatment. These are pretty impressive early data, measured by any yardstick.

Activity in RCC

There has been loads of activity in renal cell carcinoma, and another traffic jam of agents that eventually will be sorted out.

It is a delight to see real progress, sustained responses, and continued academic and clinical reward for all the soldiers who labored for decades in the quest for active agents ... and also the newbies who have been able to ride their coattails.

That said, I suspect we are all familiar with the hallmark publication from Majean and colleagues a couple years ago that demonstrated definitively that initial nephrectomy adds nothing to the survival achieved in metastatic renal cell carcinoma by treatment with sunitinib (Sutent, Pfizer) — in contrast to the earlier SWOG study that showed initial nephrectomy is beneficial when using less active systemic agents.

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This was a well-designed, appropriately powered prospective study of 450 patients that showed noninferiority of sunitinib alone (median survival, 18.4 months) compared with the surgery-sunitinib combination (median survival, 13.9 months).

This has saved countless patients from undergoing unnecessary surgery when they are sufficiently fit to tolerate one of the targeted agents. It is, thus, perplexing to see the oral presentation at the ASCO GU meeting of a propensity score-based retrospective analysis of immune checkpoint inhibitors or targeted therapies with or without preceding cytoreductive nephrectomy, which suggested a possible survival benefit from surgery.

Of course, the data needed presentation, but surely not at a keynote oral session, given that the data so easily could have been confounded by the retrospective propensity matching and the obvious risks for case selection biases. I don’t see this as changing the paradigm, or even throwing it into significant question.

Until next year ... hopefully

It will be interesting to see how my education fares when I “attend” the ASCO Annual Meeting virtually.

One of the strengths of in-person meetings is the ability to gain a deeper level of understanding, often acquired as the result of a challenging or polemical question or two (although I note that millennials avoid polemics at all costs) after a purported home-run presentation.

I’m not sure how that will play online. But hopefully, as the U.S. president has promised us a vaccine and active anti-COVID-19 therapy by the end of this year, we will all be able to gather and learn in Chicago (and elsewhere) this time next year ... unless there is no vaccine, and the rush to reopen America defeats this noble aim.

References:

Marshall CH, et al. Abstract 130. Presented at: Genitourinary Cancers Symposium; Feb. 13-15, 2020; San Francisco.

Méjean A, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1803675.

Rosenberg JE, et al. J Clin Oncol. 2019;doi:10.1200/JCO.19.01140.

Rosenberg JE, et al. Abstract 441. Presented at: Genitourinary Cancers Symposium; Feb. 13-15, 2020; San Francisco.

Sweeney CJ, et al. Abstract CT014. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).

Sweeney CJ, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1503747.

Tagawa ST, et al. Abstract 354. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

For more information:

Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, is HemOnc Today’s Chief Medical Editor for Oncology. He also is president of Levine Cancer Institute at Atrium Health. He can be reached at derek.raghavan@atriumhealth.org.

Disclosure: Raghavan reports no relevant financial disclosures.