Article

Key Trial Updates Confirm and Clarify Treatment Approaches Across Genitourinary Cancers

Matthew Galsky, MD, highlights updates in metastatic urothelial cancer treatment, as well as the evolution of PARP inhibitors and the optimal use of intensified triplet therapy in prostate cancer.

Matthew Galsky, MD

Matthew Galsky, MD

The final read out of phase 3 data from the IMvigor130 trial (NCT02807636) demonstrates that adding atezolizumab to platinum-based chemotherapy does not improve overall survival in patients with metastatic urothelial cancer while extended follow-up from the CheckMate 274 trial (NCT02632409) continues to show an improvement in disease-free survival with adjuvant nivolumab in patients with muscle-invasive urothelial cancer, according to Matthew Galsky, MD.

Within metastatic urothelial cancer, final analysis of the phase 3 IMvigor130 trial (NCT02807636) demonstrated that atezolizumab (Tecentriq) monotherapy did not show an improved overall survival (OS) vs placebo plus chemotherapy in an all-comer population1, while extended follow-up of the phase 3 CheckMate274 (NCT02632409) study reinforced the efficacy of adjuvant systemic immunotherapy.2 The effect of these analyses indicates the importance of randomized trials comparing novel treatments with standard-of-care (SOC).

“We've learned a lot of important lessons about clinical trials in these disease settings, and about the accelerated approval process that continues to [reinforce the] importance of randomized studies,” ​​Galsky said regarding the recent wave of phase 3 trials integrating immune checkpoint blockade into various clinical disease states in urothelial cancer.

Meanwhile, determining the best use of current therapies is a priority within prostate cancer, as well as clarifying the relative contribution of drug components in combination strategies. Lastly, research efforts in renal cell carcinoma (RCC) are focused on the development of non-cross resistant agents and improved classification of distinct histological subtypes.

In the interview with OncLive® following a State of the Science Summit on genitourinary (GU) cancers, which he chaired, Galsky highlighted updates in metastatic urothelial cancer treatment, as well as the evolution of PARP inhibitors and the optimal use of intensified triplet therapy in prostate cancer. He also discussed avenues for future research in RCC, and how they could address unanswered questions or unmet needs in this space.

Galsky is a professor of medicine, director of genitourinary medical oncology, co-director of the Center of Excellence for Bladder Cancer, and the associate director for translational research at the Tisch Cancer Institute, Mount Sinai in New York City, New York.

OncLive: Could you expand on the updated data presented from the IMvigor130 trial at the 2023 Genitourinary Cancers Symposium? How have these datasets affected the treatment landscape for patients with urothelial cancer?

Galsky: The main updates in bladder cancer at this year's ASCO GU Meeting included subset analyses or extended follow-up from key phase 3 trials. Specifically, we saw 2 presentations from the phase 3 IMvigor130 study that randomized patients with metastatic urothelial cancer [who] were treatment naive to chemotherapy plus atezolizumab, atezolizumab alone, or chemotherapy alone. That study had co-primary endpoints of progression-free survival [PFS] and OS in patients randomized to chemotherapy [plus] atezolizumab vs chemotherapy. That [first] analysis had to be positive for a subsequent planned hierarchical analysis to take place. In that comparison, PFS met statistical significance, and there was an improvement in PFS with chemotherapy plus atezolizumab vs chemotherapy. That [result] was published in The Lancet a few years ago.

At the time of the interim analyses, OS showed a similar effect size, but the P value has always been slightly above the threshold required for statistical significance. We've been waiting for this final OS analysis, [which] was presented at this year's meeting. The hazard ratio for OS in the study was 0.83, but the P value just missed that pre-specified value for statistical significance. Unfortunately, both IMvigor130 and the phase 3 KEYNOTE-361 [NCT02853305] trial testing platinum-based chemotherapy plus immune checkpoint inhibitor [ICI] blockade versus platinum-based chemotherapy alone, did not show an improvement in OS.

A second presentation related to [IMvigor130] had to do with one of the other comparisons which couldn't be formally addressed because of the hierarchical statistical analysis plan. That was the comparison of single-agent atezolizumab vs chemotherapy. That analysis was done on an exploratory basis. There was no significant difference in survival [between] patients randomized to frontline atezolizumab vs platinum-based chemotherapy, but early portions of the [survival] curves favored chemotherapy. [Considering] the fact that crossing over of the curves occurred late, and [that] there's an initial benefit to getting chemotherapy in the majority of patients, platinum-based chemotherapy remains the [standard of care] in patients with metastatic urothelial cancer.

There was another pre-specified exploratory analysis [for IMvigor130 that] was the last analysis in the hierarchy and couldn't be tested formally. It was asking that same question [and comparing] single-agent atezolizumab vs platinum-based chemotherapy in patients with high PD-L1 expression. There, the curves started to separate early in favor of atezolizumab. If you take that one step further and restrict that analysis to patients who are cisplatin-ineligible, the curves are separated even more. Then you really see an effect favoring atezolizumab.

Long story short, atezolizumab plus chemotherapy did not improve OS in IMvigor130 even though PFS was statistically improved. Atezolizumab vs chemotherapy [also showed] no major difference in OS, but initial portions of the curve favor chemotherapy. [Therefore], single-agent atezolizumab should not be used in an all-comer population. In the PD-L1–high subset, there does seem to be a benefit from single-agent atezolizumab vs chemotherapy, particularly in cisplatin-ineligible patients, but those [data were from] an exploratory analysis. [Notably], Genentech voluntarily withdrew this indication for atezolizumab in 2022.

What key follow-up data from the CheckMate 274 trial were presented at this year’s meeting?

The other update that we saw at this year's meeting was extended follow-up from CheckMate 274. This is a randomized, phase 3 study of adjuvant nivolumab [Opdivo] vs placebo in patients with muscle-invasive urothelial cancer and a high risk for recurrence after surgery. High recurrence risk is defined by pathological T2 or above disease in patients who had neoadjuvant cisplatin-based chemotherapy, or pathological T3 and higher disease in the absence of neoadjuvant chemotherapy for patients who are cisplatin-ineligible. We've seen disease-free survival [(DFS) findings] from this study. DFS in the all-comer population and in patients with tumors with high PD-L1 expression were the co-primary end points of this study. Initial data from this study at a median follow-up of about 5.3 months [were] published in the New England Journal of Medicine, and showed a significant improvement in DFS with adjuvant nivolumab vs placebo. That led to the FDA approval of nivolumab in this setting.

Now we see extended follow-up from the study, with a median follow-up of about 3 years. The effect size for DFS in the all-comer population and in the subset of patients with high PD-L1 expression [was] incredibly consistent with what was seen in the initial results. [That] is encouraging, because this is an adjuvant treatment that's given for a fixed duration of 1 year. Even after completing therapy, the benefit is sustained, [which is] an important metric in terms of an adjuvant therapy. A large number of secondary or exploratory end points showed almost identical effect size, [including] non–urothelial tract recurrence-free survival, distant-metastasis free survival, etc. OS is an event-driven end point in this study, and the number of events has not yet been met to formally perform the OS analysis.

Could you summarize the bladder cancer case study presented by Scot Niglio, MD, of NYU Langone Health? What treatment options are currently available for patients who are cisplatin-ineligible in this disease setting?

The case had to do with a patient who had metastatic urothelial cancer and was cisplatin-ineligible. The optimal treatment of patients with metastatic urothelial cancer who are cisplatin-ineligible has changed dramatically in the past several years. It's been a bit of a seesaw, in terms of new data [supporting the] approval of new therapies, [only for those] approvals [to be] rescinded based on evolving data from randomized settings.

We discussed the optimal treatment of a patient who presents in this context today, and there are several potential treatment options. One potential treatment option is platinum-based chemotherapy with gemcitabine/carboplatin [as the most common choice], followed by switch-maintenance ICI blockade with avelumab [Bavencio]. That strategy is supported by level 1 evidence. Single-agent ICI blockade is a potential option but is [primarily] reserved for patients who are chemotherapy-ineligible, which is certainly a difficult population to define.

The third option is the new kid on the block. This is the combination of enfortumab vedotin-ejfv [Padcev] plus pembrolizumab [Keytruda]. This is based on cohort K of the randomized phase 1/2 EV-103/KEYNOTE-869 study [NCT03288545] in the frontline metastatic setting for cisplatin-ineligible patients. [The study was] trying to assess the contribution of components of enfortumab vedotin and pembrolizumab or enfortumab vedotin alone. That study really supported what we had previously seen with cohort A of EV-103. [Cohort A had a] much smaller sample size, [but] reported a response rate of over 70% [with] enfortumab vedotin and pembrolizumab in the setting. [That was] unprecedented in this patient population. The results of cohort K support that observation, [as] the response rate comes close to what we saw in the smaller cohort.

Ultimately, this combination received accelerated approval in [the metastatic] setting. This is a new treatment option for patients with metastatic urothelial cancer who are cisplatin-ineligible. The data, [including the] response proportions and durations, are compelling. We've learned that randomized datasets comparing novel treatments with SOC [agents] are still important. This will be assessed in the [phase 3] EV-302 study [NCT04223856] comparing enfortumab vedotin and pembrolizumab vs platinum-based chemotherapy in an all-comer population. That's a study with definitive endpoints.

As discussed by your colleague Scott T. Tagawa, MD, MS, FACP, of Weill Cornell Medicine, where have PARP inhibitors come into focus in metastatic castrate-resistant prostate cancer (mCRPC)?

In metastatic prostate cancer, there's been a series of new treatment approaches in the past few years. Subsequently, many clinical trials are trying to determine the best setting to use these novel therapies. Everything is moving up earlier.

Current classes of new therapies for metastatic prostate cancer include PARP inhibitors, radioligand therapies directed at prostate-specific membrane antigen [PSMA], and novel immune therapies such as bispecific T-cell engagers. The evolution of data with PARP inhibitors has been quite interesting, because this is really the first personalized therapy in prostate cancer based on the presence of a somatic or germline alteration mutation. We now know that such alterations are much more common in patients with metastatic prostate cancer than we once thought. Now we have data for using PARP inhibitors as single agents in patients in the pre- and post-chemotherapy setting.

Evolving data [also] suggest that using PARP inhibitors plus treatments directed at the androgen-receptor [AR] signaling axis could potentially be beneficial, even in an unselected patient population. In that last category, we're still trying to determine the best path forward [for] the use of these regimens in an all-comer population, but PARP inhibitors have become part of the standard treatment approach for patients with tumors harboring alterations in DNA damage response genes, particularly BRCA2 alterations.

When considering an intensified treatment approach for patients with metastatic hormone-sensitive prostate cancer (mHSPC), which patients may benefit most from triplet vs doublet therapy as per the presentation given by David R. Wise, MD, PhD, NYU Langone Health?

[Based on] a series of phase 3 studies in patients with mHSPC, we know that giving a next-generation therapy directed at the AR signaling axis on top of traditional GnRH analogs or antagonists results in improved survival. That's been true with both lyase inhibitors and with AR inhibitors. We also know that treatment with chemotherapy in that setting improves survival with docetaxel. A major question has been: what about giving docetaxel plus AR-signaling inhibitors plus GnRH analogues/antagonists? We now have a few randomized datasets which address that question. [These data] suggest that there is an improvement in outcomes in patients who receive triplet therapy.

The limitation of current data is that there's still a question regarding the contribution of components. We know about GnRH analogues/antagonists plus docetaxel and GnRH analogues/antagonists plus docetaxel plus AR signaling inhibitors. What we don't know is how the doublet of GnRH analogues/antagonists plus AR signaling inhibitors compares with the triplet regimen. That being said, the data are compelling. In patients with high-risk mHSPC and high-volume disease, there certainly [should be] discussion of the risks and benefits of giving triplet therapy [considering] the context and limitations of available data.

Based on the presentation given by Mark N. Stein, MD, of Columbia University Medical Center, why is it important to develop more specific disease classifications for non–clear cell RCC?

Non-clear cell RCC is a heterogeneous term describing entities that are distinct in terms of their pathogenesis, molecular context, and natural history. Non–clear cell RCC is not very common. This heterogeneity of the disease coupled with the uncommon nature [can] cause difficulties in [conducting] prospective clinical investigations. For pragmatic reasons, [conducting a prospective clinical trial] has often required pooling these entities, although we know that they're not exactly the same. Of course, the better that we can define the molecular basis for these entities, [the less this will be necessary]. Much of that work has already been done, and we know the molecular pathogenesis for some of these entities. Unfortunately, knowledge of the molecular vulnerabilities for some subsets of kidney cancer has not yet translated into our ability to target those molecular alterations. The better that we can [define molecular subtypes in RCC], the [more] we'll be able to do future clinical trials that are rationale-directed at these patient subgroups.

Regarding the presentation given by Che-Kai Tsao, MD, of Icahn School of Medicine at Mount Sinai, what unmet needs remain for the treatment of patients with advanced RCC?

[There has been much] activity in the development of new therapies for metastatic RCC. Multiple phase 3 trials have met their primary end points, which is exciting and different from what we've seen in some other GU cancers these past several years. Despite that [progress], the actual number of distinct therapeutic classes that are non-cross resistant in metastatic kidney cancer remains limited. We have multi-targeted VEGF TKIs, although these are somewhat distinct in terms of the kinases that they inhibit. As a result, there is some difference in terms of the activity and [adverse effect (AE)] profiles of these drugs. [Still], they encompass a single class of therapies.

We have ICIs, PD-L1 or PD-1 inhibitors or CTLA-4 blockade, and then we have mTOR inhibitors. HIF inhibitors are coming [down the pike], and there's lots of excitement [about] those therapies. We know that combination therapy in the frontline metastatic setting is important. Ultimately, we need additional non–cross-resistant drugs [with] different mechanisms of action and different AE profiles to make our combination approaches even more effective.

Could you briefly discuss on any trials in the GU cancer space that are being conducted at your institution?

The first clinical trial involves rapid sequencing of therapies for metastatic kidney cancer. This trial is being run by Che-Kai Tsao, MD, of Icahn School of Medicine. The rationale for this treatment is that we typically give systemic therapies until progression. There is some concern that giving treatment until progression might breed resistance to treatment. There is an alternative approach which involves giving treatment for a fixed period and cycling treatments with different mechanisms of action. [This] attempt [aims to] kill non-cross resistant cells, but not continue treatment indefinitely such that it breeds resistance.

The other study that we're excited about is called the MODERN (A032103) study. This study will be initiated [by] the Alliance for Clinical Trials in Oncology, should be accessible by all groups though the National Cancer Institute National Clinical Trials Network. This is a study seeking to employ adjuvant ICI blockade in a more precise way. It involves performing circulating tumor DNA [ctDNA] testing after surgery for bladder cancer and in patients with high-risk pathological features. If there's detectable ctDNA, patients are randomized to treatment with SOC nivolumab or nivolumab plus the LAG-3 inhibitor relatlimab. If patients have undetectable ctDNA after surgery, then they're randomized to receive SOC nivolumab or surveillance with the initiation of nivolumab at the time of molecular conversion from an undetectable ctDNA assay to a detectable ctDNA assay. The prognostic effect of ctDNA testing in the postoperative setting in urothelial cancer [has] been demonstrated in a series of observational studies and retrospective studies. We need to prospectively validate these findings and establish the clinical utility of this testing, to incorporate it into our treatment approaches.

​​

Disclosures: Dr Galsky reported serving as a consultant or in an advisory role for Aileron Therapeutics, Astellas Pharma, AstraZeneca, Basilea, BioMotiv, Bristol Myers Squibb, Dendreon, Dracen, Dragonfly Therapeutics, EMD Serono, Genentech, Gilead Sciences, GlaxoSmithKline, Incyte, Infinity Pharmaceuticals, Inovio Pharmaceuticals, Janssen, Lilly, Merck, Novartis, NuMab, Pfizer, Seattle Genetics, Silverback Therapeutics, Urogen pharma; he reports receiving research funding from AstraZeneca, Bristol Myers Squibb, Dendreon, Genentech/Roche, Janssen Oncology, Merck, and Novartis; he has ownership interests in Rappta Therapeutics.

References

  1. Galsky MD, Angel J, Arranz A, et al. Atezolizumab (atezo) + platinum/gemcitabine (plt/gem) vs placebo + plt/gem for first-line (1L) treatment (tx) of locally advanced or metastatic urothelial carcinoma (mUC): final OS from the randomized phase 3 IMvigor130 study. J Clin Oncol. 2023;41(suppl 6):LBA440. doi:10.1200/JCO.2023.41.6_suppl.LBA440
  2. Bamias A, Davis ID, Galsky MD, et al. Final overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy (chemo) in untreated locally advanced or metastatic urothelial carcinoma (mUC) from the phase 3 IMvigor130 study. J Clin Oncol. 2023;41(suppl 6):LBA441. doi:10.1200/JCO.2023.41.6_suppl.LBA441
  3. Galsky MD, Witjes AA, Gschwend JE, et al. Extended follow-up results from the CheckMate 274 trial. J Clin Oncol. 2023;41(suppl 6):LBA443. doi:10.1200/JCO.2023.41.6_suppl.LBA443
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