Disclosures: Joshi reports no relevant financial disclosures.
October 27, 2020
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Advances in treatments for genitourinary malignancies provide silver lining to 2020

Disclosures: Joshi reports no relevant financial disclosures.
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This year has seen some groundbreaking advances in genitourinary oncology, particularly in the fields of prostate, kidney and urothelial cancers.

Monika Joshi, MD, MRCP
Monika Joshi

The results of multiple trials became available to the scientific community — including results of the phase 3 JAVELIN Bladder 100 trial in metastatic urothelial cancer, presented during the plenary session of the ASCO20 Virtual Scientific Program — and the FDA approved some novel treatment indications.

The following article highlights these developments and provides personal insights about them and how they’ll change treatment of genitourinary cancer, while considering any lingering clinical dilemmas. Additionally, I’ll provide guidance on how to interpret the data and their implications in the everyday clinical field.

Positive, negative trials in bladder cancer

In January, the FDA approved pembrolizumab (Keytruda, Merck) for high-risk nonmuscle-invasive bladder cancer (MIBC) refractory to bacillus Calmette-Guérin based on results of the phase 2 KEYNOTE-057 study, which showed a complete response (CR) rate of 40.6% with median duration of response of 16.2 months. Even though this gives these patients an alternative to surgery, the long-term benefits are still unknown, and this may be an inferior choice to surgery, a curative approach.

In April, results of the OLYMPUS study led the FDA to approve mitomycin gel (Jelmyto, UroGen Pharma) for the treatment of low-grade upper tract urothelial cancer. This prospective study showed a CR rate of 59% at 3 months with 85% durability at 12 months. Although long-term follow-up results are awaited, these data demonstrate that half of these patients could have disease eradication and avoid nephroureterectomy, a finding that has life-changing implications. This may be a reasonable option for some of our patients who are not good candidates for surgery or who wish to delay surgery.

In localized bladder cancer, we learned that adjuvant PD-L1 therapy is not beneficial, as results of the phase 3 IMvigor010 study of adjuvant atezolizumab (Tecentriq, Genentech/Roche) vs. placebo in high-risk muscle-invasive urothelial cancer showed no DFS improvement.

In September, Bristol Myers Squibb announced that CheckMate 274, a phase 3 study evaluating nivolumab’s (Opdivo, Bristol Myers Squibb) role in adjuvant setting for high-risk MIBC, met its primary endpoint for improving DFS. Details of the study results should be presented soon.

However, conflicting results from two large phase 3 studies tell us that the efficacy of checkpoint inhibition for high-risk MIBC varies and raises the possibility of differences in patient population between these two studies, rather than the actual dissimilarity between an anti PD-1 vs. anti PD-L1 drug. Nevertheless, at this point, there is no FDA approval for adjuvant immunotherapy in this setting.

In metastatic urothelial cancer (mUC), switch maintenance with PD-1-directed therapy among patients who had disease control following upfront chemotherapy resulted in a higher objective response rate (pembrolizumab, 23% vs. placebo, 10%) and a 2.4-month improvement in PFS (5.4 months vs. 3 months).

Also, the phase 3 JAVELIN Bladder 100 study showed OS of 21.4 months with maintenance avelumab (Bavencio; EMD Serono, Pfizer) compared with 14.3 months with best supportive care after responding to initial induction platinum-based chemotherapy. Twelve-month OS among PD-L1-positive patients was 79.1% compared with 60.4% with best supportive care. Although previous studies have reported efficacy with second-line therapy using checkpoint inhibition, this was the first to report a significant OS benefit in the upfront maintenance setting among patients who responded to platinum-based therapy.

This certainly has corresponded with an increase in the median survival of newly diagnosed patients with mUC who responded to platinum therapy, from approximately 15 months to an estimated 25 to 27 months — 21.4 months seen in this trial plus 4 to 6 months for chemotherapy — with avelumab maintenance, which I consider an important landmark difference. Based on these results, maintenance therapy with avelumab following response to platinum-based chemotherapy is a new standard of care for mUC and should always be offered unless contraindicated.

At ESMO Virtual Congress 2020 in September, Loriot and colleagues presented the results of TROPHY-U-01, a study evaluating the role of sacituzumab govitecan (Trodelvy, Immunomedics), an antibody-drug conjugate, for patients with mUC who progressed after prior platinum-based chemotherapy and immunotherapy-based treatments. These refractory patients showed a 27% response rate, with a 5% CR rate and a 22% partial response rate. Median PFS was 5.4 months with median OS of 10.5 months.

This treatment appears promising and its efficacy is being verified in a phase 3 study. The only drug currently approved by the FDA in the refractory mUC setting following chemotherapy and immunotherapy, regardless of FGFR status, is enfortumab vedotin-ejfv (Padcev; Astellas, Seattle Genetics).

PARP and beyond in prostate cancer

Although the FDA approved enzalutamide (Xtandi; Astellas, Pfizer Oncology), apalutamide (Erleada, Janssen Oncology) and darolutamide (Nubeqa, Bayer) for nonmetastatic castration-resistant prostate cancer (CRPC) based on improvement in metastasis-free survival (MFS), OS benefit was questionable.

Previous results of the randomized phase 3 ARAMIS study, which evaluated the efficacy of darolutamide vs. placebo in nonmetastatic CRPC, demonstrated a benefit in MFS (40.4 months vs. 18.4 months). The final analysis of the trial, presented at ASCO, showed OS — a secondary endpoint of this study — also significantly improved with darolutamide (3-year OS, 83% vs. 77%; HR = 0.69, 95% CI, 0.53-0.88). These results solidified the advantage of using darolutamide in nonmetastatic CRPC.

Two targeted agents — poly(ADP-ribose) polymerase (PARP) inhibitors — also received FDA approval for metastatic CRPC (mCRPC) tumors that harbor mutations in BRCA1/BRCA2 or have homologous recombination repair (HRR) gene defects.

In May, olaparib (Lynparza; AstraZeneca, Merck) received approval based on the results of the PROfound study, a biomarker-selected study that enrolled men with mCRPC who had progressed on either abiraterone or enzalutamide. The study consisted of two cohorts — cohort A, which included men with at least one alteration in BRCA1/BRCA2 or ATM, or cohort B, which consisted of men who had alterations in any of the 12 selected prespecified HRR genes.

Researchers randomly assigned men to olaparib vs. physician’s choice of abiraterone or enzalutamide. Median PFS was almost doubled in cohort A (7.4 months vs. 3.6 months), with a 3.4-month improvement in median OS (18.5 months vs. 15.1 months) with olaparib. Researchers also noted an overall benefit of 2.3 months in radiographic PFS with olaparib.

Similarly, results of the TRITON2 study led to the accelerated approval of rucaparib (Rubraca, Clovis Oncology) for men with mCRPC whose tumors harbor BRCA1/BRCA2 mutations. Study results demonstrated an ORR of 44% in this patient population, with 56% of men having a duration of response of longer than 6 months.

It is important to note that in both studies, men with BRCA1/BRCA2 alterations derived the most benefit from PARP inhibitors. These studies have not only changed the landscape of DNA repair, particularly for BRCA1/BRCA2-driven mCRPC tumors, but also have also highlighted the significance of biomarker testing in this setting. All men with mCRPC should get their tumor tested for HRR gene defects, as some could qualify for PARP inhibitors that have the potential to provide meaningful clinical benefit.

Ipatasertib (Genentech/Roche), an oral agent that targets the PI3K/AKT pathway, is another drug that shows promise in mCRPC. The phase 3 IPATential150 study assessed the combination of ipatasertib plus abiraterone acetate and steroids vs. placebo plus abiraterone acetate and steroids for untreated men with mCRPC (see page 15). The researchers of this study used PTEN tumor loss as one of the stratification factors, with coprimary endpoints of radiographic PFS (rPFS) among PTEN-loss tumors and among all patients.

Results, also presented at ESMO, showed a 2-month rPFS benefit with the ipatasertib combination (18.5 months vs. 16.5 months; P = .0335) among men with PTEN loss. Subgroup analyses showed that men who received prior taxane-based therapy did not derive benefit from this combination, although this cohort was underrepresented in this study compared with everyday clinical practice.

This combination is currently not approved by the FDA and the survival data are immature. However, it is encouraging to see the expansion of treatment options for men with poor-risk mCRPC and PTEN loss.

Additionally, the results of randomized phase 2 TheraP trial, presented at ASCO, showed more men with progressing mCRPC achieved PSA decline of 50% or greater with lutetium-177-labeled prostate-specific membrane antigen (PSMA)-617 (LuPSMA) than with cabazitaxel (Jevtana, Sanofi Genzyme; 66% vs. 37%).

Prostate cancer cells express PSMA, whereas lutetium-177 is the beta radiation particle that is tagged with the PSMA-identifying agent PSMA-617. This new therapy, LuPSMA, can kill PSMA-positive prostate cancer cells.

PSMA-directed therapies are an important new class of drugs for metastatic CRPC that could improve survival of this lethal disease. Results of larger studies, such as VISION (NCT03511664), could shape the future of mCRPC treatment.

None of these radionuclide-directed therapies for prostate cancer is currently FDA approved, but our hope is that some of these may get approval in the near future.

Immunotherapy, TKIs for renal cell cancer

Multiple combinations containing checkpoint inhibitors have been approved by the FDA for renal cell cancer.

Two phase 3 studies — KEYNOTE-426 and JAVELIN Renal 101 — showed the combination of a checkpoint inhibitor with the second-generation tyrosine kinase inhibitor axitinib (Inlyta, Pfizer Oncology) improved the overall outcome for patients with newly diagnosed metastatic renal cell cancer (mRCC).

Earlier reports from KEYNOTE-426 demonstrated that the combination of pembrolizumab and axitinib significantly improved ORR, PFS and OS vs. sunitinib (Sutent, Pfizer) as upfront therapy for mRCC. Further follow-up data from the trial, presented at ASCO, showed the combination maintained its superiority over sunitinib in terms of ORR (60.2% vs. 39.3%), CR rate (8% vs. 3%) and 1-year OS (90% vs. 74%).

One-third of this study’s participants consisted of a favorable-risk group, for whom there was no OS benefit. The overall improvement in outcome appeared driven by intermediate- and poor-risk disease, per International Metastatic Database Consortium (IMDC) risk score.

At this year’s ESMO, Choueiri and colleagues presented results of the phase 3 CheckMate 9ER trial evaluating the combination of nivolumab and cabozantinib (Cabometyx, Exelixis) vs. sunitinib as upfront treatment for advanced or metastatic RCC (see related article).

As first-line therapy, this combination demonstrated benefit in terms of ORR (55.7% vs. 27.1%), PFS (median, 16.6 months vs. 8.3 months; HR = 0.51; 95% CI, 0.41-0.64) and OS (medians not reached; HR = 0.6; 98.89% CI, 0.4-0.89) compared with sunitinib. The benefit appeared consistent across all subgroups.

Currently, there are no data to show whether these immunotherapy-TKI combinations are better than the immunotherapy doublet of ipilimumab (Yervoy, Bristol Myers Squibb) and nivolumab as front-line therapy for mRCC. But, one could select the combination of TKI plus PD-1 inhibitor for patients who have IMDC poor-risk disease to provide them the benefit of two active agents in RCC.

However, both the immunotherapy doublet and the combination of checkpoint inhibitor plus TKI appear to be effective treatment options for patients with mRCC. The exact sequencing of these therapies is still unclear and results from some ongoing studies, like PDIGREE, may be able to help us understand this better.

Data also were released this year from three clinical studies investigating immunotherapy rechallenge in the salvage setting, with results showing efficacy of adding ipilimumab for patients with mRCC not responding to PD-1-directed therapy alone. Although the studies differed in design, they all showed that the use of delayed ipilimumab confers only modest benefit in the second line and beyond, and the maximum benefit of the immunotherapy doublet lies in the upfront setting for mRCC.

In summary, immunotherapy doublet when possible, should be offered to patients with mRCC in the upfront setting.

New TKIs have emerged this year for mRCC. One such agent, savolitinib (AZD6094/HMPL-504, Chi-Med), a TKI that targets MET, showed promising efficacy among patients with papillary RCC harboring a MET gene abnormality; follow-up studies are needed. Among 60 patients, PFS appeared superior among those randomly assigned to savolitinib vs. sunitinib (7 months vs. 5.6 months).

Two studies presented at ASCO showcased the development of new therapies in hereditary kidney cancer.

A phase 2 study that evaluated the combination of bevacizumab (Avastin, Genentech) and erlotinib (Tarceva, Genentech) showed response rates of 64% in advanced hereditary leiomyomatosis and papillary renal cell cancer and 37% in nonhereditary papillary RCC.

A study of the novel hypoxia inducible factor (HIF)-2 alpha inhibitor MK-6482 (Merck) in von Hippel-Lindau-associated nonmetastatic RCC showed an ORR of 27.9%, with a decrease in tumor burden observed among 86.9% of patients.

In another study reported in February at Genitourinary Cancers Symposium, MK-6482 demonstrated an ORR of 24% among patients with heavily pretreated mRCC across all IMDC risk groups. Further studies of this agent will shed more light on its efficacy.

These new TKIs show promising efficacy in rare forms of RCC that could change the way we treat these cancers in future.

These exciting developments provided a silver lining to a year overshadowed by the COVID-19 pandemic and will allow providers to offer a wider range of treatment options to patients with resulting improvement in treatment outcomes.

References:

Abida W, et al. Abstract 846PD. Presented at: European Society for Medical Oncology; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

Choueiri TK, et al. Abstract 611. Presented at: Genitourinary Cancers Symposium; Feb. 13-15, 2020; San Francisco.

Choueiri TK, et al. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2020.2218.

De Bono J, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1911440.

Galsky MD, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.03091.

Gul A, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.03315.

Kleinmann N, et al. Lancet Oncol. 2020;doi:10.1016/S1470-2045(20)30147-9.

The following were presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020:

Atkins MB, et al. Abstract 5006.

Balar AV, et al. Abstract 5041.

Fizazi F, et al. Abstract 5514.

Hofman MS, et al. Abstract 5500.

Hussain MH, et al. Abstract 5000.

Jonasch E, et al. Abstract 5003.

McKay RR, et al. Abstract 5005.

Plimack ER, et al. Abstract 5001.

Powles T, et al. Abstract LBA1.

Srinivasan R, et al. Abstract 5004.

The following were presented at European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020:

Choueiri TK, et al. Abstract 696O_PR.

De Bono J, et al. Abstract LBA4.

Loriot Y, et al. Abstract LBA24.