There is a distinct pattern of metastasis associated with prognostic significance in renal cell carcinoma (RCC), and identifying underlying genetic components of those metastases could help inform personalized treatment strategies for this patient population, according to Rana R. McKay, MD.

Various genes of intertest have been identified in various metastases of the lung, liver, bone, and more, and McKay said understanding the common mutations related to these sites can provide valuable insight into treatment.

“The sights of metastases have different genomic underpinnings compared with the kidney, and that could impact outcomes,” said McKay, a medical oncologist and associate professor of medicine at Moores Cancer Center, University of California San Diego Health.

 during the 2022 Genitourinary Cancers Symposium, McKay discussed findings from a real-world study on genomic alterations of metastases in RCC,

 the rationale of the phase 3 COSMIC-313 trial (NCT03937219) in patients with previously untreated advanced or metastatic RCC, plus findings from the phase 1/2 COMRADE trial (NCT03317392) in patients with metastatic castration-resistant prostate cancer (mCRPC).

: Could you provide an overview of the real-world data set that you presented at the symposium, which analyzed genomic alterations and transcriptional signatures across the spectrum of metastatic sites in patients with RCC?

: We know from several large databases that site of metastasis is prognostic in RCC. We and others have demonstrated that bone and liver metastases are associated with worse prognosis, and pancreas metastases are associated with better prognosis. We are lacking with regard to underlying data as to why that is. Why does site of metastasis matter?

We sought to utilize a commercial database through [Caris Life Sciences] of RCC tumors from primary and distant metastases to comprehensively characterize the molecular features across sites of metastases. Our analysis was 3-pronged in nature. We looked at mutations and polymorphisms using initially a 592-gene panel and whole exome sequencing. We did whole transcriptome sequencing and PD-L1 expression on over 650 distinct samples.

We identified that there are mutations and, [in] the distribution of mutations of selected genes across different metastatic sites, there are common mutations that exist in kidney cancer, whether they are in the primary [tumor] or in the metastasis. Those are 

We also realized that there are differences when you look at the various sites compared with the kidney, and we did observe that 

 alterations were more frequent in the lung, bone, [and] endocrine glands relative to the kidney. 

 seemed to be more prevalent in lung and gastrointestinal [GI] metastases. 

, for example, was more prevalent in the bone and central nervous system [CNS], and 

 was more prevalent in liver and CNS [metastases].

The other thing that we did was look at the [phase 3 IMmotion151 trial (NCT02420821) led by Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, examining] gene clusters across the different sites of metastasis. We did see differences in the molecular subgroup classifications between primary and metastatic sites. As we look at the breakdown more granularly, lung, bone, liver, skin, and GI metastases seem to have divergent molecular subtypes relative to the kidney, lung, and bone, [which] were enriched for the angiogenic stromal signature, whereas liver [tissue] seemed to be more enriched for the complement/Ω-oxidation signature.

That is important because these signatures have been associated with differential outcomes to treatments. For example, the angiogenic stromal signature seems to be associated with a more robust response to tyrosine kinase inhibitor [TKI]-based therapies, whereas a T-effector proliferative signature seems to be associated with a more robust response to immunotherapy. The complement/Ω-oxidation signature, for example, is 1 of those signatures that has been shown to be associated with poor outcomes in general.

As we think about the application of this data, understanding the molecular underpinnings for organotropism is going to help us personalize strategies for patients with kidney cancer in the future.

What are the next steps toward the application of these data?

What is lacking from this data set right now is clinical outcomes. We do not have the overlay of, ‘How did these patients do in this dataset? How did those patients with bone metastases that had X signature do with immunotherapy? How did they do with targeted therapy?’ Applying the clinical outcomes will help us understand how to optimize therapy selection for patients based on sites of metastases for any given patient.

What should be emphasized about the results of this study?

Although there are some similarities between the kidney and distant metastatic sites when we are looking at various genes of interest, there are key differences with the predominance of select genes in different metastatic sites relative to the kidney. There are differences between the gene signatures in different metastatic sites relative to the kidney and the tumor microenvironment, which could play a role with regard to treatment outcomes.

You also presented a poster at the symposium on the phase 1/2 COMRADE trial, which examined olaparib (Lynparza) and radium-223 dichloride (Xofigo) in mCRPC. Could you provide an overview of this study?

This was a trial that was looking to assess the potential synergy of radium-223, which is an alpha-emitting radiopharmaceutical that induces DNA damage with olaparib, which is a PARP inhibitor that prevents repair of single-strand DNA breaks within the tumor. The trial was designed as a phase 1/2 study. Phase 1 [was designed] to test the safety of the combination and the recommended phase 2 dose [RP2D] for olaparib, when olaparib is given in combination with radium-223. Phase 2 was designed to test the efficacy [of the combination].

Phase 1 has been completed, and [in] the data presented at the symposium, we identified that olaparib when combined with radium-223 was safe, and that the RP2D was 200 mg twice daily. In our data set, we presented the correlative data for all 12 patients who had enrolled onto the phase 1 portion of the trial. Patients underwent genomic testing to define their homologous recombination repair [HRR] gene status. Of 9 patients who had enough tissue to be profiled, 2 were found to have pathogenic HRR gene alterations. One was in 

 alteration had a progression-free survival [PFS] of 11.8 months compared with 3.1 months for the patient with the 

[We also looked] at RAD51 staining in archival tumor specimens. These are still early [data], but there was an individual with a 

 alteration that was negative for RAD51, which is a functional readout of HRR, suggesting that there is a homologous recombination deficiency, and that individual had a PFS of 10.2 months.

The summary here is that olaparib and radium-223 can be safely combined. We have identified the RP2D for the 2 drugs in combination, and there are biomarkers that are currently being developed to try to understand responses to therapy and enriching for responses.

What are the next steps for this combination?

Phase 2 is accruing patients. We have about 60 patients who have enrolled onto the phase 2 study. There will be an upcoming interim analysis to look at efficacy with radiographic PFS as a key primary end point for the trial. The results of the randomized phase 2 portion hopefully will be telling regarding next steps and moving this combination forward.

How could positive data from the phase 2 trial and future studies affect the treatment paradigm?

A lot of studies are looking at the combination of PARP inhibitors with various agents that have already demonstrated efficacy in prostate cancer. Data were presented with abiraterone acetate [Zytiga] combined with olaparib at this year’s meeting, and olaparib and other PARP inhibitors are being combined with other agents. There is a potential for synergy with olaparib and radium-223 in a safe manner that could be practice changing, but it is still very early.

In terms of ongoing trials, there’s the phase 3 COSMIC-313 trial, which is examining the combination of cabozantinib (Cabometyx) with nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with advanced RCC. What is unique about this study?

This is a modern-day study that is looking at evaluating the triplet of ipilimumab/nivolumab [with] cabozantinib, where the cabozantinib starts simultaneously with ipilimumab/nivolumab, compared with ipilimumab/nivolumab alone. This is 1 of the first trials being designed with a modern-day control arm of ipilimumab/nivolumab, as opposed to a single-agent TKI in the frontline setting.

The trial is enrolling patients with intermediate- and poor-risk clear cell RCC. The trial has completed accrual, and we are eagerly awaiting the results. The results of this study have the potential to be practice changing. Since 2018, we have moved into doublets in the frontline space, and with time, the field is now pushing into triplets for a select population of patients.

What has it been like to see research advanced at such a fast pace in RCC?

Over the past almost 2 decades, we have seen the life expectancy for patients with advanced kidney cancer lengthen and lengthen and lengthen and that is because of advances in the therapeutic paradigm, which is excellent to see. We still have work to do, but it has been exciting to be a part of that process.

Are there any specific areas within RCC that warrant additional research?

The big question is what to do in the adjuvant setting. We saw data at the symposium that were presented from the phase 3 KEYNOTE-564 study [NCT03142334] with updated 30-month follow-up of the efficacy of pembrolizumab [Keytruda] given in the adjuvant setting. There are a lot of questions to be had around the role of adjuvant immunotherapy. What is the right patient population? [Should we give a] single agent or can we combine [agents in the adjuvant setting]?

These are the next questions in the field. For patients that have received adjuvant immunotherapy, what is the best frontline option for them? Do the data of all the [immunotherapy] combinations in frontline studies still apply to somebody who is not naïve to checkpoint inhibitors and has progressed despite checkpoint inhibitors? As the treatments improve, new questions come up, and the landscape is shifting.

Are there any other clinical trials you want to highlight?

We presented the data about the differential outcomes for sites of metastases, and historically, patients with bone metastases have done poorly in kidney cancer. We have designed a study that is looking at cabozantinib with or without radium-223, which is a liquid radiopharmaceutical, to see if we can improve symptomatic skeletal-related events with the combination. The trial is called the phase 2 RadiCaL trial [NCT04071223]. It is open through the cooperative groups being led through Alliance. We are eager to promote the study and encourage involvement.

McKay RR, Barata PC, Elliott A, et al. Molecular alterations across sites of metastasis in patients with renal cell carcinoma (RCC). 

. 2022;40(suppl 6):287. doi:10.1200/JCO.2022.40.6_suppl.287

McKay RR, Xie W, Ajmera A, et al. Updated biomarker results from a phase 1/2 study of olaparib and radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases (COMRADE). 

. 2022;40(suppl 6):119. doi:10.1200/JCO.2022.40.6_suppl.119

Articles

Rana R. McKay, MD, discusses findings from a real-world study on genomic alterations of metastases in renal cell carcinoma, the rationale of the phase 3 COSMIC-313 trial in patients with previously untreated advanced or metastatic RCC, plus findings from the phase 1/2 COMRADE trial in patients with metastatic castration-resistant prostate cancer.

Analysis of Genomic Alterations in Metastases Could Help Inform Treatment in RCC

Treatment with a tyrosine kinase inhibitor (TKI) remains the standard of care for patients with metastatic renal cell carcinoma (RCC) who progress following immunotherapy in the frontline setting. However, ongoing clinical trials are investigating whether immunotherapy agents could still play a role after progression, according to Moshe Ornstein, MD, MA.

For example, the phase 3 CONTACT-03 trial (NCT04338269) is exploring the combination of cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) vs cabozantinib monotherapy, and the phase 3 TiNivo-2 trial (NCT04987203) is investigating tivozanib (Fotivda) plus nivolumab (Opdivo) vs tivozanib monotherapy. Ornstein noted pending data from both studies could help answer a pivotal question in the treatment space for RCC.

“We have seen tremendous progress in the treatment of patients with metastatic clear cell RCC who receive immunotherapy-based combinations up front,” Ornstein said. “We have ipilimumab [Yervoy] and nivolumab, axitinib [Inlyta] and pembrolizumab [Keytruda], cabozantinib and nivolumab, lenvatinib [Lenvima] and pembrolizumab, etc. [We have] all these immunotherapy-based combinations, but a real question that remains unanswered in the field is what the role of immunotherapy [is] in patients whose cancer has progressed having already received immunotherapy.”

 during the 2022 Genitourinary Cancers Symposium, Ornstein, a genitourinary medical oncologist at the Taussig Cancer Institute at Cleveland Clinic, discussed the trials exploring second-line immunotherapy in patients who have progressed on immunotherapy, plus key clinical trial data on kidney cancer presented at the conference and other pressing areas of need for research in RCC.

: Could you provide an overview of the phase 2 NeoAvAx trial (NCT03341845) which investigated neoadjuvant avelumab (Bavencio) and axitinib in patients with localized RCC who were at high risk for relapse following nephrectomy?

: There is a lot of talk about adjuvant therapy for patients who are at high risk of recurrence after their kidney cancer is removed, but there is a lot of rationale to give therapy before surgery, as well. [One] of the reasons to give therapy before surgery is to downsize a tumor to make the surgery either easier or to allow for additional nephron sparing. [Surgeons] are not going to have to remove as much of the kidney as one might otherwise have to remove.

Another reason to give therapy before surgery, especially when it comes to giving immunotherapy before surgery, is that, theoretically, giving immunotherapy when the primary tumor is in place produces better results. There are some data from other tumor types that [show that] giving immunotherapy before surgery can improve disease-free survival [DFS], compared [with] when you give it after surgery, and that is what this phase 2 trial did with axitinib and avelumab. Axitinib is a VEGFR TKI, and avelumab is a PD-L1 inhibitor. Combinations of these treatment classes are approved for patients with metastatic kidney cancer.

We know axitinib and avelumab, when combined, are active for patients with metastatic kidney cancer. The question was: If we select patients in the neoadjuvant setting, will there be a response in those patients, as well? [This study included] patients who were at high risk of relapse, patients who had clinically node-positive disease, a high T stage, a high Fuhrman grade, and treated them with 6 doses of avelumab. [Avelumab] was given every other week for 6 cycles, so basically 12 weeks of treatment before surgery. Axitinib, which is a pill, was given at the standard dosing with dose-escalation parameters built into the trial.

What this study was looking at was a primary end point of objective response rate [ORR]. If patients get this combination before surgery and then get a scan at the time of surgery: What is the rate of patients who have a 30% tumor burden decrease? Secondary end points [included] DFS, overall survival [OS], safety, and tolerability.

What were some of the key efficacy findings that read out from this trial?

A total of 40 patients were enrolled in the trial. The median age of these patients, [like] what we generally see in our kidney cancer clinics, was 63 years. [It was] predominantly a male population [as] 70% of the patients in the trial were males. The population did span the range of high-risk categories: 43% of the patients had node-positive disease, 20% were T4 [positive], and 28% had Fuhrman grade 3 or 4 disease.

The high-level results are as follows: 12 of the 40 patients [30%] had what is considered a partial response. The ORR was 30%. Interestingly, 10 of those patients, so 83% of the patients who had a response, remained disease free at the time of study follow-up. The median DFS and the median OS were not reached. However, at a median follow-up of close to 2 years, recurrence occurred only in approximately one-third of patients. In other words, two-thirds of patients remained disease free at that time of follow-up.

What was the biggest takeaway from the data found in this trial with this combination?

Any time we talk about a neoadjuvant or an adjuvant trial in patients who have localized kidney cancer, we must take the efficacy in the context of the toxicity. For patients who have metastatic kidney cancer, most of those patients are not going to be cured. We will accept the higher rate of toxicity. But when we talk about a patient who has localized kidney cancer, even though many of those patients will have disease recurrence, many of them are going to be cured without treatment. We must set the bar for toxicity a little lower for what we are willing to accept.

What is important in this trial is that this combination before surgery was well tolerated. There were not any unexpected toxicities; all serious adverse [effects] were resolved. Also important in the neoadjuvant setting is the toxicity at the time of surgery, and there did not appear to be any notable surgical complications.

There is activity for this combination prior to surgery, and it does not come with worrisome toxicity. Although it is not a standard of care to give this combination prior to surgery for patients with localized kidney cancer, it does establish a standard where this can be done safely if it is needed in the right patient. There are some data now to support its use, but it is not a standard of care.

Regarding the 30-month follow-up of the phase 3 KEYNOTE-564 trial (NCT03142334) presented at the symposium, could you highlight some notable takeaways from the data read out of that study?

KEYNOTE-564 was a randomized trial in which patients who had some degree of high-risk kidney cancer, either intermediate-high risk, high risk, or metastatic disease that was resected after surgery. Such patients who had surgery were then randomized to receive either pembrolizumab or placebo for 1 year. The initial results had previously been reported, and the initial results have already demonstrated a DFS [improvement] in this population. [Initial results] led to the FDA approval of pembrolizumab for patients with high-risk kidney cancer after nephrectomy. [Pembrolizumab] has become a standard in many clinics for patients who have high-risk kidney cancer. After their surgery, they are receiving pembrolizumab for 1 year.

The primary analysis was done with 24 months of follow-up, and the updated analysis was done with 30 months of follow-up. What is important to note with the follow-up is that DFS was still strong, with a hazard ratio of 0.63. The 24-month DFS rate was 78.3% in patients receiving pembrolizumab and 67.3% in patients who were on the placebo arm, showing a nice risk reduction for patients receiving pembrolizumab after surgery.

One of the interesting things reported was [data on] some of the subgroups. For patients with intermediate-high risk, the benefit was about 9% in terms of the difference in recurrence between patients receiving pembrolizumab vs placebo. The risk difference between the patients receiving pembrolizumab and placebo was even greater in patients with higher risk and in patients with M1 no evidence of disease. In other words, patients who had some metastatic disease that was resected after surgery.

This highlights that patient selection here is critical. This is probably not going to be the right treatment for all patients, but as patients move into higher-risk groups, the DFS benefit becomes more significant. Importantly, we always talk about sarcomatoid features, and patients who did have sarcomatoid features had a significant difference in the DFS benefit between receiving pembrolizumab and placebo.

[Regarding] OS, it is still early. Fortunately, not enough events have occurred, although the curves have started separating and remain separated at the 2-year and 3-year marks. These data further solidified pembrolizumab for 1 year after surgery in patients with high-risk kidney cancer, but an individual discussion on a case-by-case basis is important to have with patients to balance that benefit of DFS with the still unknown OS benefit.

Could you provide an overview of the objectives for the CONTACT-03 and TiNivo-2 trials?

There are 2 trials that are investigating [immunotherapy following progression on immunotherapy] in a randomized fashion, and the data from those trials will go a long way to drive clinical decision making in the clinic. One of those trials is the CONTACT-03 trial, and that trial is randomizing patients who have already received an immunotherapy-based treatment for metastatic kidney cancer to receive either cabozantinib, which is a standard-of-care monotherapy, or cabozantinib with atezolizumab, a PD-L1 inhibitor.

Another trial investigating this question is the TiNivo-2 trial, which is investigating tivozanib as a monotherapy, [which is] a highly selective VEGFR TKI, vs the combination of tivozanib with nivolumab. [This trial is] once again looking to answer that critical question of [whether there is] a role for immunotherapy-based treatment in patients whose kidney cancer has already progressed on immunotherapy. The standard of care right now is essentially just to give a TKI, and this will help drive whether we give immunotherapies in combination with TKIs, or [whether there is] any role for immunotherapy in what is technically immunotherapy-resistant kidney cancer.

What areas still need to be addressed in future research in RCC?

A lot of progress has been made over the past 5 to 10 years in the treatment of patients with metastatic kidney cancer, but there are still a lot of questions that the field has, and we look forward to seeing the research and the clinical trials that yield these results to benefit our patients. Much of the progress has been in treatment-naïve metastatic RCC. Patients receiving their first line of therapy are now getting immune-based combinations, but what to do and how to manage those patients after their cancer progresses on frontline therapy remains a challenge.

Most of the agents that are available for refractory RCC have response rates of maybe 20% to 30% and a short progression-free survival, and at that point, patients tend to cycle from 1 therapy to the next. Is there some form of novel therapy? Is there some therapy that can produce a durable benefit in patients with refractory RCC? Those studies are ongoing.

These trials that have led to the remarkable results we see these days are predominantly in clear cell kidney cancer. Although clear cell RCC makes up 75% to 80% of all patients with RCC, that still leaves a lot of patients who do not have clear cell kidney cancer and need treatment options. We look forward to seeing additional research to help benefit those patients with non–clear cell kidney cancer.

Another area of research is the duration of therapy. In many of these treatment options, patients are treated until they have toxicity that they cannot handle any more or until their cancer gets worse, and they do not have a chance to get off therapy. [It is important to keep] thinking about trial designs that take advantage of treatment-free intervals [and] thinking about the duration of therapy patients need to have that durable response.

Lastly, we still [think of] kidney cancer in a one-size-fits-all approach. At the Genitourinary Cancers Symposium 2022, a lot of data was presented on prognostic and predictive biomarkers, genomics, etc., but we do not have a personalized approach to know which treatment option is likely to benefit which patients. I am excited about trials that are emerging that are going to be genomically driven, that are going to harness the biology of an individual patient’s tumor to help guide what treatment that patient needs. Ultimately by doing that, we can improve response rates, we can improve cure rates, we can improve deep, durable responses, and that is ultimately the goal: to provide long-term benefits for our patients.

Bex A, Abu-Ghanem Y, Van Thienen JV, et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). 

. 2022;40(suppl 6):289. doi:10.1200/JCO.2022.40.6_suppl.289

Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: results from 30-month follow-up of KEYNOTE-564. 

. 2022;40(suppl 6):290. doi:10.1200/JCO.2022.40.6_suppl.290

Moshe Ornstein, MD, MA, discusses trials exploring second-line immunotherapy in patients who have progressed on immunotherapy, plus key clinical trial data on kidney cancer and other pressing areas of need for research in renal cell carcinoma.

Immunotherapy Could Still Play a Role After Progression in Patients With RCC

The FDA approvals of immunotherapy-based combinations as frontline therapy led to a substantial increase in their use in patients with metastatic renal cell carcinoma (mRCC) in the community setting, leading to a greater use of TKI monotherapy as second- and third-line therapies, according to findings from a study that were presented at the 2022 Genitourinary Cancers Symposium.

The results highlighted a trend toward the increased use of dual checkpoint inhibition and checkpoint/VEGF inhibition after their FDA approvals in April 2018 (third/fourth quarter 2018, 46.6%; first and second quarter 2019, 50.2%) and April 2019 (first and second quarter 2019, 7.7%; third and fourth quarter 2019, 32.2%), respectively.

Notably, the use of single-agent TKIs decreased from 53.4% in the third and fourth quarter of 2018 to 42.1% in the first and second quarter of 2019 to 24.0% in the third and fourth quarter of 2019.

“This large real-world study examined use of new FDA-approved mRCC treatments and their impact on [the] treatment paradigm. The results show a rapid adaptation of these newer treatments in the community oncology settings,” the study authors wrote.

Several checkpoint inhibitor and TKI combinations have been approved by the FDA for the frontline treatment of patients with mRCC over past few years. However, data are few and far between regarding the real-world use and sequence of available regimens in mRCC, particularly in the community setting.

To better understand current community practice patterns, investigators compiled data from The US Oncology Network, pooling more than 1300 providers from over 480 sites in the United States from January 1, 2018, to December 31, 2020.

Eligible patients included those with mRCC who had received either the combination of ipilimumab (Yervoy) plus nivolumab (Opdivo), pembrolizumab (Keytruda) plus axitinib (Inlyta), or avelumab (Bavencio) plus axitinib, or single-agent axitinib, cabozantinib (Cabometyx), pazopanib (Votrient), or sunitinib (Sutent) as frontline therapy until September 30, 2020.

A total of 1538 patients were eligible for inclusion in the study. Most patients had received dual checkpoint inhibition (41.6%; n = 641) followed by TKI monotherapy (40.2%; n = 618) and a checkpoint/VEGF inhibitor combination (18.1%; n = 279). However, by the third quarter of 2020, most patients were receiving dual checkpoint inhibition (41.9%) or checkpoint/VEGF inhibition (31.3%) followed by TKI monotherapy (26.9%).

The median patient age was 67.4 years (interquartile range, 57.8-76.0). Most patients were male (69.7%; n = 1,076) and White (69.5%; n = 1,081); 79.8% (n = 1208) had clear cell histology.

Most patients (86.6%; n = 1338) had intermediate- and poor-risk disease according to the International Metastatic RCC Database Consortium risk model.

Over the course of the study period, 34.7% of patients (n = 535) received second-line therapy: 19.0% (n = 53) in the checkpoint/VEGF group; 38.5% (n = 247) in the dual checkpoint inhibition group; and 38.0% (n = 235) in the TKI monotherapy group. A total of 34.7% of patients (n = 186) received third-line therapy; less than 42.0% (n = 12), 33.6% (n = 83), and 38.7% (n = 91) across the groups, respectively.

The most common second-line therapies in patients who received prior dual checkpoint inhibition were cabozantinib (48.6%; n = 120) and pazopanib (12.1%; n = 30); the most common third-line treatments were cabozantinib (20.5%; n = 17), everolimus (Afinitor) plus lenvatinib (Lenvima; 18.1%; n = 15), and axitinib (10.8%; n = 9).

In patients who received prior checkpoint/VEGF inhibition, the most common second-line treatments were cabozantinib (50.9%; n = 27) and ipilimumab plus nivolumab (22.6%; n = 12); less than 5 patients (<42.0%) received cabozantinib as third-line therapy.

Patients who received a single-agent TKI in the frontline setting received nivolumab (44.7%; n = 105) and ipilimumab plus nivolumab (19.6%; n = 46) most commonly in the second-line setting; the most common third-line treatments were cabozantinib (22.0%; n = 20) and axitinib (16.5%; n = 15).

“Longer follow-up is needed to assess their clinical impact and optimal treatment strategy in subsequent setting[s],” concluded the study authors.

Shah NJ, Sura S, Shinde R, et al. Real-world assessment of changing treatment patterns and sequence for patients with metastatic renal cell carcinoma (mRCC) in the first-line (1L) setting. 

. 2022;40(suppl 6):302. doi:10.1200/JCO.2022.40.6_suppl.302

The FDA approvals of immunotherapy-based combinations as frontline therapy led to a substantial increase in their use in patients with metastatic renal cell carcinoma in the community setting, leading to a greater use of TKI monotherapy as second- and third-line therapies.

Real-World Study Shows Fast Uptake of Immunotherapy-Based Combinations in Frontline RCC 

The addition of olaparib (Lynparza) to durvalumab (Imfinzi) did not result in a significant prolongation in progression-free survival (PFS) compared with durvalumab alone in patients with previously untreated, platinum-ineligible metastatic urothelial carcinoma, missing the primary end point of the phase 2 BAYOU trial (NCT03459846).

The data, which were presented during the 

, showed that the median investigator-assessed PFS with the doublet (n = 78) in the intent-to-treat (ITT) population was 4.2 months (95% CI, 3.6-5.6) vs 3.5 months (95% CI, 1.9-5.1) with durvalumab alone (n = 76; HR, 0.94; 95% CI, 0.64-1.39; log-rank 

However, data from a prespecified secondary analysis suggested that olaparib plus durvalumab had a potential PFS benefit in a subgroup of patients with homologous recombination repair (HRR) mutations. In this population, the median PFS achieved with the doublet (n = 17) was 5.6 months (95% CI, 1.9-8.1) vs 1.8 months (95% CI, 1.7-2.2) with single-agent durvalumab (n = 14; HR, 0.18; 95% CI, 0.06-0.47; log-rank 

“The PFS results suggest a potential role for PARP inhibitors in the treatment of metastatic urothelial carcinoma with HRR mutations, and further investigation is warranted,” Jonathan E. Rosenberg, MD, chief of the Genitourinary Oncology Service in the Division of Solid Tumor Oncology, and Enno W. Ercklentz Chair at Memorial Sloan Kettering Cancer Center, said in an oral presentation on the data.

Patients with metastatic urothelial carcinoma are known to have a poor prognosis, particularly those who cannot tolerate platinum-based chemotherapy, Rosenberg said. For these patients, atezolizumab (Tecentriq) and pembrolizumab (Keytruda) are given, irrespective of PD-L1 status; however, a high unmet need for additional therapeutic options remains.

Defects in DNA damage repair occur in approximately 24% of patients with urothelial carcinoma, and the dysregulation of DNA repair genes has been associated with poorer outcomes. Notably, these defects are known to make cancer cells sensitive to PARP inhibitors. As such, investigators hypothesized that HRR mutations and PARP inhibition could strengthen the antitumor response achieved with immune checkpoint inhibitors.

To this end, BAYOU sought to enroll approximately 150 patients with unresectable, stage IV urothelial carcinoma, a transitional cell carcinoma of the bladder, renal pelvis, ureter, or urethra. Patients needed to be at least 18 years of age and have an ECOG performance status ranging from 0 to 2.

Study participants were randomized 1:1 to receive either intravenous (IV) durvalumab at a dose of 1500 mg every 4 weeks plus oral olaparib at a twice-daily dose of 300 mg or durvalumab alone. Key stratification factors included HRR status (mutant vs wild-type) and Bajorin risk index (0 vs 1 vs 2).

The primary end point of the trial was PFS by RECIST v1.1 criteria and per investigator assessment. Key secondary end points comprised PFS by RECIST v1.1 criteria in the subgroup of patients with HRR mutations, overall survival (OS), duration of response (DOR), objective response rate (ORR), and PFS at 6 months by RECIST v1.1 criteria in both the ITT population and the HRR-mutated subset. Other end points of interest included safety and tolerability.

The data cutoff date was October 15, 2020. The median follow-up in the investigative arm was 9.8 months (range, 0.0-29.0) vs 10.7 months (range, 1.0-29.0) in the control arm.

Those who received the doublet were slightly older than those who received durvalumab monotherapy, at a median of 79 years (range, 47-89) vs 72 years (range, 45-88). Slightly more than half of patients in both arms were male. In the investigative arm, 51% of patients were White, 49% were Asian, and none were Black or African American; in the control arm, these rates were 46%, 51%, and 3%, respectively.

Regarding ECOG performance status, 15% of patients who received olaparib plus durvalumab had a status of 0, 38% had a status of 1, and 44% had a status of 2. Of those who were given durvalumab monotherapy, 18% had an ECOG performance status of 0, 45% had a status of 1, and 37% had a status of 2. Most patients in both arms had pure transitional cell carcinoma.

Moreover, 67% of patients who received the doublet had visceral metastases, and 33% had lymph-node only disease; these rates were 63% and 37%, respectively, in those who received the monotherapy. In the investigative and control arms, 11.5% and 10.5% of patients, respectively, received previous therapy.

In the investigative arm, 21% of patients did not have any Bajorin risk factors, 49% had 1 risk factor, and 31% had 2. In the control arm, 24% did not have Bajorin risk factors, 47% had 1, and 29%, and 2. Seventy-eight percent of patients in the doublet arm had HRR wild-type disease, and 22% had HRR-mutated disease; in the control arm, these rates were 82% and 18%, respectively.

The 20 most frequent gene mutations demonstrated a pattern that proved to be consistent with what has previously been observed in bladder cancer, according to Rosenberg. Across all patients, the most common HRR gene mutations were loss of p53 function (59.5%) and TERT promoter mutations (55.6%).

Utilizing the validated FoundationOne assay, investigators tested tumor samples for loss of function alterations in the following 15 prespecified HRR genes: 

. HRR mutations were found in 7 of the 15 genes analyzed. The most frequent included 

, which was identified in 8.5% of all tumors and in 41.9% of patients in the HRR-mutated subset, as well as 

, which was found in 4.6% of all tumors and in 22.6% of those in the HRR-mutated subgroup.

Exploratory subgroup analyses also showed that PFS favored olaparib/durvalumab over durvalumab alone in those with a Bajorin risk index of 0 (HR, 0.42; 95% CI, 0.18-0.92). However, PFS appeared to favor single-agent durvalumab over the doublet in those with HRR wild-type disease (HR, 1.29; 95% CI, 0.85-1.96), in those with a Bajorin risk index of 1 (HR, 1.90; 95% CI, 1.07-3.49), and in those with a Bajorin risk index of 2 (HR, 1.19; 95% CI, 0.63-2.28).

Data from the prespecified secondary analysis of OS showed that olaparib plus durvalumab did not result in improved OS vs durvalumab monotherapy in the ITT population. Specifically, the median OS with the doublet 10.2 months (95% CI, 7.0-13.9) vs 10.7 months (95% CI, 7.2-17.3) with durvalumab alone (HR, 1.07; 95% CI, 0.72-1.61; log-rank 

The same was true in the subgroup of patients with HRR wild-type disease. The median OS with olaparib plus durvalumab (n = 61) was 10.9 months vs 13.7 months with single-agent durvalumab (n = 62; HR, 1.35; 95% CI, 0.85-2.16). However, the doublet (n = 17) was found improve median OS in the subset of patients with HRR-mutated disease vs the monotherapy (n = 14), at 8.6 months vs 5.8 months, respectively (HR, 0.56; 95% CI, 0.25-1.23).

The addition of olaparib to durvalumab resulted in an ORR of 28.2% in the ITT population vs 18.4% with durvalumab alone. In the investigative arm, 3.8% of patients achieved a complete response, 24.4% had a partial response (PR), 34.6% achieved stable disease (SD) for at least 7 weeks, 32.1% experienced disease progression, and 5.1% were not evaluable. The median DOR in the investigative arm was 8.9 months (range, 4.7-12.1) vs 14.8 months (range, 7.5-17.2) in the control arm.

In the HRR-mutated subset, the combination produced an ORR of 35.3% vs 0% with durvalumab alone. Among those who responded to the doublet, 35.3% achieved a PR and 29.4% had SD for 7 weeks or longer. Moreover, 29.4% had progressive disease and 5.9% were not evaluable. The median DOR with olaparib/durvalumab was 6.7 months (range, 3.7-12.0) in this subset.

No new safety signals were observed with the combination of olaparib and durvalumab, according to Rosenberg. Any-grade treatment-related adverse effects were experienced by 72.4% of patients who received the doublet (n = 76) vs 60.5% of those given the monotherapy (n = 76).

The most common toxicities observed in the investigative arm included anemia (any grade, 23.7%; grade 3 or 4, 6.6%), nausea (any grade, 19.7%; grade 3 or 4, 1.3%), fatigue (any grade, 15.8%; grade 3 or 4, 1.3%), decreased appetite (any grade, 10.5%), diarrhea (any grade, 10.5%), and hypothyroidism (any grade, 9.2%). In the control arm, the most common toxicities included anemia (any grade, 13.2%; grade 3 or 4, 1.3%), pruritus (any grade, 10.5%), fatigue (any grade, 6.6%), rash (any grade, 5.3%), nausea (any grade, 3.9%), hypothyroidism (any grade, 3.9%).

One death was reported in the durvalumab monotherapy arm, and this was because of anemia.

Rosenberg JE, Park SH, Dao TV, et al. BAYOU: a phase II, randomized, multicenter, double-blind, study of durvalumab (D) in combination with olaparib (O) for the first-line treatment of platinum-ineligible patients with unresectable, stage IV urothelial carcinoma (UC). 

. 2022;40(suppl 6):437. doi:10.1200/JCO.2022.40.6_suppl.437.

The addition of olaparib to durvalumab did not result in a significant prolongation in progression-free survival compared with durvalumab alone in patients with previously untreated, platinum-ineligible metastatic urothelial carcinoma.

Frontline Olaparib/Durvalumab Misses PFS End Point in Platinum-Ineligible Metastatic Urothelial Carcinoma

F-rhPSMA-7.3 imaging displayed a clinically meaningful correct detection rate (CDR), meeting the prespecified threshhold of assessing suspected biochemical recurrence in prostate cancer, according to findings from the phase 3 SPOTLIGHT trial (NCT04186845) presented at the ASCO 2022 Genitourinary Cancers Symposium.

“There’s excellent image quality,” said coordination investigator David M. Schuster, MD, FACR, Emory University School of Medicine, “and also the potential for low urinary secretion, which, as we know, is important for imaging prostate cancer.”

F-rhPSMA-7.3, an investigational prostate‐specific membrane antigen (PSMA)‐targeted radiohybrid (rh) PET imaging agent, demonstrated an overall evaluable detection rate (DR) in this study population of 83% by majority read.

“Up to 40% of patients who undergo radical prostatectomy, and up to 50% of patients who undergo radiation therapy will develop local or distant recurrences within 10 years, and the ability to determine the extent and location of recurrent prostate cancer to inform appropriate clinical management for these men is key for physicians and their patients,” Schuster, said in a press release issued by Blue Earth Diagnostics.

 “Conventional imaging techniques have many limitations in prostate cancer identification and localization, and greater imaging accuracy is needed throughout the care continuum, to optimize therapeutic decision‐making.”

Therefore, researchers aimed to evaluate 

F‐rhPSMA‐7.3 PET imaging as a potential decision‐making aid to determine suspected biochemical recurrence of prostate cancer across a wide PSA range.

In the prospective, multicenter, single‐arm imaging study, conducted in the United States and Europe, 389 men (median PSA, 1.10 ng/mL [range, 0.03-134.6]) were enrolled. To meet the inclusion criteria, patients had to be male, over the age of 18, have a history of localized prostate cancer with prior curative intent treatment, have an elevated PSA suspicious of biochemical recurrence, and be potentially eligible for salvage therapy with curative intent.

Following an IV administration of 296 MBq 

F-rhPSMA-7.3, patients underwent PET for 50 to 70 minutes. At 60 days post-PET, investigators performed image-guided biopsies of PET lesions. At 90 days post-PET, investigators performed any confirmatory imaging. Scans were evaluated by 3 blinded central readers, with a final consensus of “majority read”. Each patient also underwent a separate Standard of Truth (SoT) via Truth Panel.

The coprimary endpoints were patient level CDR, or percentage of patients scanned with 1 true positive lesion, and region level positive predictive value (PPV), which was determined for all PET positive regions combined using histopathology and/or conventional imaging as a composite SoT. Analysis of these metrics were also performed in a group of patients with a histopathology-only SoT.

A strict imputation method was implemented in both primary end points, in which PET-positive lesions that were proven on conventional imaging were considered false positive, and the prespecified statistical threshold for CDR and PPV were set to 36.5% and 62.5%, respectively.

Results showed that the patient level CDR was 56.8% (95% CI, 51.6%-62.0%) in the 366 men (median PSA, 1.27 ng/mL [range, 0.03-134.6]) with a composite SoT. While this finding met the prespecified threshold, the region level PPV did not (59.7%; 95% CI, 54.7%-64.7%]).

However, Schuster said, “Keep in mind [that] the data from this cohort with a composite Standard of Truth are limited by the high proportion of scans, especially those of the prostate [and] bed that relied on conventional imaging, which is a suboptimal Standard of Truth in itself.”

Furthermore, investigators found that the patient level CDR was 81.2% (95% CI, 69.9%-89.9%) and the region level PPV was 71.6% for the subset of patients with a histopathology-only SoT. Both percentages would have met their prespecified thresholds.

There were no serious adverse events (AEs) related to 

F-rhPSMA-7.3. The most frequently reported AEs were hypertension (1.8%; n = 7), diarrhea (1.0%; n = 4), injection site reaction (0.5%; n = 2), and headache (0.5%; n = 2). In total, 4.1% of patients (n = 16) had at least 1 AE that could possibly be related to the novel theranostic.

In his concluding remarks, Schuster said, “Together, these data support the clinical utility of 

F-rhPSMA-7.3 PET in men with recurrent prostate cancer across a wide PSA range.”

F-rhPSMA-7.3 PET in Patients with Suspected Prostate Cancer Recurrence: Results from a Phase 3, Prospective, Multicenter Study (SPOTLIGHT). Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract #9.

Blue Earth Diagnostics Press Release. Blue Earth Diagnostics Announces Key Results from Phase 3 SPOTLIGHT Study of 

F‐rhPSMA‐7.3, an Investigational PET Imaging Agent, in Biochemical Recurrence of Prostate Cancer. Published February 15, 2022. Accessed February 18, 2022. 

The utilization of 18F-rhPSMA-7.3 imaging displayed a clinically meaningful correct detection rate.

18F-rhPSMA-7.3 Imaging Favorable Detection Rates in Men with Recurrent Prostate Cancer

The androgen receptor inhibitor darolutamide (Nubeqa) demonstrated continued efficacy and safety in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) who have comorbidities or concomitant medications, according to data presented at the 2022 ASCO Genitourinary Cancers Symposium.

For the study, patients with nmCRPC from the phase 3 ARAMIS trial (NCT02200614) were randomized 2:1 to receive either darolutamide (n = 955) or placebo (n = 554) while continuing treatment with androgen deprivation therapy. At the final data cut-off date of November 15, 2019, overall survival (OS) and adverse events (AEs) were evaluated in patients with a median of 6 or fewer or more than 6 comorbidities and 10 or fewer or more than 10 concomitant medications. Comorbidities evaluated included metabolic, cardiovascular, and other (osteoarthritis and arthralgia and back pain, benign prostatic hyperplasia, constipation and gastroesophageal reflux, and renal insufficiency). Concomitant medication classes/subclasses included gastrointestinal/metabolic, cardiovascular (antihypertensives and non-antihypertensives), pain/inflammation, and urologic.

“More than 50% of the patients in the ARAMIS trial, which was a very significant number of patients…had a minimum of 6 or more comorbidities of significance,” commented study coauthor Neal Shore, MD, FACS, said. Specifically, 795 of the total cohort of 1509 patients had at least 6 comorbidities, and 813 patients had received at least 10 concomitant medications.

The investigators reported that in patients with at least 6 and more than 6 comorbidities, darolutamide prolonged OS compared with placebo (HR, 0.65 and 0.73, respectively). The OS benefit for darolutamide was found to be consistent in patients with metabolic, cardiovascular (CV), and other comorbid disorders (HR range, 0.39-0.88). OS was also prolonged in patients receiving at least 10 and more than 10 concomitant medications (HR, 0.76 and 0.66, respectively). “Subgroups of [patients] receiving concomitant medications for gastrointestinal/metabolic disorders, CV disease, urologic disorders, and pain/inflammation achieved similar OS benefit with [darolutamide vs placebo] (HR range, 0.45–0.80),” wrote the authors.

Regarding AEs, 447 patients with at least 6 comorbidities (83%) and 366 patients with more than 6 comorbidities (90%) experienced any AE, vs 242 (74%) and 195 patients (88%) receiving placebo, respectively. A total of 127 patients with at least 6 comorbidities (24%) and 124 patients with more than 6 comorbidities (31%) experienced a grade 3 or 4 AE, vs 58 (18%) and 61 (28%) patients receiving placebo, respectively. A total of 43 patients with at least 6 comorbidities (8%) and 42 patients with more than 6 comorbidities (10%) experienced an AE leading to permanent study drug discontinuation, vs 20 (6%) and 28 patients receiving placebo (13%).

A total of 371 patients (77%) taking at least 10 concomitant medications and 442 patients taking more than 10 concomitant medications (95%) experienced any AE, vs 184 (68%) and 248 (91%) of patients receiving placebo, respectively. Sixty-seven patients (14%) taking at least 10 concomitant medications and 183 patients (39%) taking more than 10 concomitant medications experienced a grade 3 or 4 AE, vs 36 (13%) and 82 patients (30%) receiving placebo, respectively. Finally, 35 patients taking at least 10 concomitant medications (7%) and 50 patients taking more than 10 concomitant medications (11%) experienced an AE leading to permanent study drug discontinuation, vs 17 (6%) and 29 patients (11%) receiving placebo, respectively.

“I think what we're showing here is that the overall survival benefit, as well as the safety analysis, regardless of the number of comorbidities, was rather significant,” Shore said.

Fizazi K, Shore ND, Smith MR, et al. Efficacy and safety outcomes of darolutamide in patients with nonmetastatic castration-resistant prostate cancer with comorbidities and concomitant medications from ARAMIS. Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract 256.

The androgen receptor inhibitor darolutamide demonstrated continued efficacy and safety in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) who have comorbidities or concomitant medications

Darolutamide Maintains Efficacy in Patients with Comorbidities, Concomitant Medications in Nonmetastatic CRPC