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GU Cancers: A Year In Review

RCC Highlights

Negative results from the Phase III IMmotion010, CheckMate-914 Part A, and PROSPER trials call into question the benefit of adjuvant IO therapy, especially in lower risk patients.

Though the COSMIC-313 triplet underperformed relative to nivo + ipi with respect to ORR, CR, and tolerability, it did show a significant PFS benefit and will continue to IA2 prior to FDA submission in the hopes of improving OS.


Topic 1: RCC

The Future of Adjuvant Therapy:

In 2021, the PIII KEYNOTE-564 study demonstrated an improved DFS benefit for pembrolizumab vs active surveillance in int/high-risk localized RCC patients following nephrectomy. This positive result and subsequent approval were major strides for the RCC treatment paradigm, ushering in the first true adjuvant standard of care. Contrastingly in 2022, three PIII adjuvant IO studies failed to demonstrate a statistically meaningful DFS benefit vs observation. The failures of CheckMate-914 (nivolumab + ipilimumab), IMmotion010 (atezolizumab), and PROSPER (nivolumab), call into question the efficacy benefit of adjuvant IO therapy. In light of these recent failures, the RCC community will look to KEYNOTE-564 follow-up analyses with the hopes of seeing a significant OS advantage. In the meantime, patient selection for adjuvant therapy is very top of mind given the mixed pivotal study results, especially in the intermediate risk, large, T3 subgroup of the ITT population.

“These IO failures were very disappointing for the field overall as there remains major unmet need for localized RCC patients, hopefully the KN564 study can show a survival benefit to solidify it as SOC.” – US KOL

COSMIC-313 triplet underperforms in IA1:

The PIII COSMIC-313 study is the first pivotal trial to include a contemporary standard of care comparator arm as it evaluates nivo + ipi + cabo vs nivo + ipi in int/poor-risk 1L aRCC. While there was a great deal of excitement for the novel triplet approach, the results proved to be underwhelming. The trial successfully met its primary PFS endpoint, though dramatically underperformed in ORR, CR rate, and toxicity relative to SOC IO/TKIs. Exelixis has announced that the trial will continue on to IA2 in the hopes of producing an OS benefit prior to submitting to the FDA for approval.

“Overall, COSMIC-313 was not necessarily a positive trial in RCC. This trial was always going to be positive in terms of PFS since it added an efficacious TKI to IO/IO, but the ORR, CR rate, and lack of OS were disappointing. We have to wait and look out for the overall survival data.” – US KOL

Novel HIF2a Inhibitors in RCC:

While 1L IO-based combinations have revolutionized the treatment paradigm and dramatically raised the efficacy bar, effective novel MOAs beyond IO and TKI are greatly needed for IO-refractory patients. Belzutifan is a novel HIF2a inhibitor that addresses a key driver of clear cell RCC with minimal toxicity. Early-phase trials in ccRCC and VHL patients have already demonstrated belzutifan’s clinical activity, though large-scale randomized study results are needed to more specifically elucidate belzutifan’s optimal role in the landscape. Given its strong tolerability, belzutifan appears to be a great drug for combination approaches. Over the next few years, several Phase III belzutifan studies will be reading out data, with the RCC field eagerly awaiting these results.

“HIF2a is the most exciting new target that we currently have in kidney cancer with proven activity across several trials. There is a very good chance that the ongoing Phase III trials will change clinical practice.” – US KOL


Bladder Highlights

Intravesical agents are an ongoing area of interest for urologists in treatment of NMIBC, especially within the BCG-unresponsive setting that has seen the recent approval of Adstiladrin (nadofaragene firadenovec).

Positive results from EV-103 / KEYNOTE-869 Cohort K support general KOL optimism for combo enfortumab vedotin (EV) + pembrolizumab and pave the way for this combo to be used as SOC 1L la/mUC treatment. Failures in IO + IO and IO + chemo combinations in la/mUC treatment further highlight the potential of ADCs in metastatic bladder cancer.


Topic 2: Bladder


Intravesical agents are being studied as monotherapies and in combination with IO across NMIBC. The recent approval of nadofaragene firadenovec in BCG-unresponsive NMIBC not only marked the first gene therapy approved in bladder cancer but also a new addition to intravesical options available to patients. Further, N-803 is an IL-15 superagonist that is being investigated in combination with BCG for the same setting; the BLA for this asset has been submitted based on Phase II/III data from QUILT 3.032. There continues to be extensive development in BCG-experienced patients given the ongoing BCG shortage in the US. Understanding and stratifying patients’ experience with BCG is a critical component to developing in this disease setting, but guidance by the FDA and perceptions of physicians differ. Specific to the BCG-unresponsive setting, the FDA does not require randomized control trials as of tet, however physicians are of the mindset that they should, especially given the recent and upcoming developments in NMIBC.

“I think the FDA is approving some therapies quite quickly. What I have seen in the last few years is that some drugs eventually take a step back after initial approval." – US Urologist


The role of immunotherapy within the muscle invasive bladder cancer (MIBC) setting is evolving and expanding, aided by biomarker analyses. Cisplatin-based chemotherapy has been SOC for MIBC as neoadjuvant treatment before radical cystectomy and now with the approval of adjuvant nivolumab through CheckMate-274 in 2021 based on DFS benefit, the therapeutic options available to patients are expanding. Physician’s debate the effectiveness of this immunotherapy in the adjuvant setting given that OS data are not yet released, despite long-term demonstrated DFS benefit. Additionally, one concern for these patients is the potential for overtreatment – especially as biomarker analyses reveal certain subgroups benefit more from adjuvant nivolumab. Given this, physicians have expressed wanting a future that is biomarker-driven. Namely, IMvigor011 is now investigating adjuvant atezolizumab in ctDNA+ patients after the failure of IMvigor010 to meet its primary DFS endpoint in a larger population. Given the one success and one failure in the adjuvant setting so far, physicians are turning to the ongoing trials in MIBC to help elucidate the potential benefit of immunotherapy in this disease setting.

“IO has been approved already in the adjuvant setting based on CM-274, but I am not in favor of using adjuvant IO for all patients. We need better patient selection.” – US Medical Oncologist

Metastatic Bladder Cancer:

Innovation in 1L metastatic bladder cancer has been difficult to achieve. Standard of care (SOC) chemotherapy has consistently proven superior to trials investigating checkpoint inhibitors as monotherapies and in combination with chemotherapy. However, what we have witnessed is that the role of antibody drug conjugates (ADCs) in this space may be the key. Excitement for PD-1 / PD-L1 combinations with chemotherapy or other immunotherapies has waned in the face of multiple failures, but it appears as if ADCs may soon disrupt the 1L SOC. For example, IMvigor130 was a confirmatory trial investigating atezolizumab monotherapy and in combination with chemotherapy for 1L treatment of metastatic bladder cancer. Upon its failure to meet its OS primary endpoint, Genentech (Roche) withdrew atezolizumab from all lines of therapy in metastatic bladder cancer treatment. Similar stories have been seen with AstraZeneca’s DANUBE, Merck’s KENYOTE-361, and BMS’ CheckMate-901 nivolumab + ipilimumab arm (failed OS in PD-L1+ patients). Whereas the investigation of enfortumab vedotin (EV) + pembrolizumab in cisplatin-ineligible 1L la/mUC patients in the EV-103 / KEYNOTE-869 has demonstrated promising clinical benefit. EV has already been approved globally in the 2L+ setting and may potentially provide the key to disrupting the 1L SOC. The BLA for this combination was accepted in December 2022 based on positive results presented at ESMO 2022, with confirmatory trial EV-302 / KEYNOTE-A39 ongoing. Physicians are confident in the data and believe that this combination has a lot of potential to change the existing treatment landscape, but are still wary of potential toxicity and downstream implications. If EV + pembro is approved in the 1L metastatic bladder cancer setting, innovation and development will need to change as research sheds more light on sequencing of therapies like CPIs and ADCs.

“All of my colleagues are ready to jump to use enfortumab vedotin + pembrolizumab, but I have a patient now that has a mixed response to this regimen. There will likely be an explosion of use on EV + P, but longevity is dependent on magnitude of benefit.” – US Medical Oncologist


Prostate Highlights

Triplet therapy was approved in mHSPC in the US based on ARASENS showing strong OS benefit of adding an NHA to chemotherapy.

Pluvicto (177Lu-PSMA-617) became the first PSMA RLT to be approved by the FDA and EMA on the basis of the VISION trial in post-NHA, post-chemo PSMA-positive mCRPC. However, Novartis experienced production issues in mid-2022, halting global PSMA RLT supply.

For PARP + NHA trials, PROpel (abi + ola) showed rPFS benefit in all-comers, TALAPRO-2 (tala + enza) had a positive readout in all-comers, and MAGNITUDE (abi + nira) demonstrated positive data in its HRRm cohort but did not show statistically significant benefit for its non-HRRm arm.


Topic 3: Prostate

Triplet Therapy

We have finally seen the approval of triplet therapy (ADT + NHA + chemo) for mHSPC with ARASENS. Based on strong results presented at ASCO GU 2022 demonstrating 32.5% OS benefit of the triplet vs. docetaxel + ADT, FDA approval occurred in August 2022. PEACE-1, a notable academic EU-based trial investigating triplet therapy in mHSPC, also showed rPFS [HR 0.54] and OS [HR 0.82] benefit in de novo mHSPC patients, who are higher-risk with shorter time to mCRPC and likely have worse survival outcomes. In terms of uptake, KOLs predict triplet therapy will likely be 10-15% of mHSPC, specifically restricted to high-volume patients who are candidates for docetaxel, which is similar to PEACE-1 inclusion criteria. They also project inclusion of triplet therapy in treatment guidelines is unlikely to increase number of patients receiving chemotherapy in mHSPC, but the strong survival benefit provides Level I evidence to layer on an NHA on top of docetaxel. Overall, this represents a major step in early treatment intensification.

“The number of doce + ADT patients will really shrink since the triplet showed unequivocal benefit, but triplet is still unlikely to be used in a majority of patients with mHSPC.” – US Medical Oncologist


In March 2022, 177Lu-PSMA-617 (Pluvicto) from Novartis was approved by the FDA through the VISION trial in post-NHA, post-chemo PSMA-positive mCRPC, and subsequently approved by EC in December 2022. This approval is practice-changing as PSMA RLT showed statistically significant rPFS and OS benefit of a novel mechanism of action, offering a new treatment alternative to heavily-pretreated patients. For Pluvicto + BSOC vs. BSOC, mOS was 15.3 mo. vs 11.3 mo. [HR 0.62] and mrPFS was 8.7 mo. vs. 3.4 mo. [HR 0.40]. While higher rate of high-grade adverse events occurred with PSMA RLT than the comparator arm (NHA), according to the TheraP trial, PSMA RLT has a more tolerable safety profile compared to chemo. Novartis faced some mid-year headwinds when it paused Pluvicto and Lutathera production given manufacturing and quality control concerns, disrupting global PSMA RLT supply and global enrollment of PSMAfore and PSMAddition. In response, KOLs have acknowledged manufacturing and production concerns with PSMA RLT, citing it is a complicated process involving agents with limited half-lives. During the second half of the year, SPLASH trial from POINT Biopharma debuted positive data from lead-in cohort and PSMAfore from Novartis met rPFS primary endpoint. Both trials are pushing to place PSMA RLT before chemo in mCRPC. In SPLASH, mrPFS for PNT2002 was 11.5 mo., which demonstrates superiority compared to post-NHA benchmarks of 3.5 – 4.2 mo. KOLs do not expect significant differences between PSMAfore and SPLASH in terms of efficacy and safety, regardless of differences in dosing and administration schedule.

“Biggest hits of 2022 are PSMA PET imaging becoming more widely available and approval of Pluvicto to treat late-stage mCRPC.”​ – US Medical Oncologist


In Q1 2022, we saw the first PARP + NHA presentation at a major congress in frontline mCRPC. From the PROpel trial (olaparib + abiraterone), we saw positive rPFS readout in an all-comer population, regardless of HRR mutation status. The PARP + NHA arm resulted in an investigator-assessed all-comers rPFS benefit ~8 mo. (mrPFS of 24.8 mo. vs. 16.6 mo. [HR 0.66]). Subgroup analysis of rPFS showed benefit in HRRm [HR 0.50] and non-HRRm [HR 0.76] patients. This is revolutionary to the usage of PARP in oncology. The MAGNITUDE trial (niraparib + abiraterone) also met its primary endpoint for the HRRm cohort, as the PARP + NHA arm resulted in a BICR-assessed rPFS benefit ~5 mo. (mrPFS of 16.5 mo. vs. 13.7 mo. [HR 0.73]). Subgroup analysis showed rPFS benefit in in BRCA1/2 [HR 0.53], but not in HRRm-negative patients [HR 1.09], introducing skepticism for the benefit of PARP + NHA in non-HRR mutated mCRPC. In October 2022, TALAPRO-2 (talazoparib + enzalutamide) announced positive readout in its all-comers arm. Following this, PARP + NHA received its first regulatory approval in December 2022 with the European Commission issuing an approval for PROpel in all-comers. This is an unprecedented development not only in terms of timing, since the FDA originally granted PROpel Priority Review and has decided to delay the decision by 3 months, but also scope of approval, since the EMA has historically provided more biomarker-restricted labels than the FDA. Axiom speculates the final OS analysis from PROpel and relative rPFS benefit from TALAPRO-2 HRRm vs. all-comers cohorts may influence the FDA’s label.

“We’re unsure if PARP has benefit in non-HRRm patients. PROpel suggests yes by rPFS, MAGNITUDE suggests no. We’re waiting on OS at ASCO GU 2023 to make a more definitive call.” – EU Medical Oncologist


A year In Review- GUCancers
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Watch Axiom's Year-in-Review, to learn more about tumor and indication-wide recaps of the most pivotal data from 2022. Pillar leads and experts from the Table will facilitate the discussion.


For Details on Axiom’s Capabilities in GU Cancers, Contact:

Hafiz Sikder –

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