Kidney Cancer NCCN Guidelines Receive Major Updates, Prostate Cancer Adds Targeted Agents

Sandy Srinivas, MD

With the movement and development of several agents and regimens in the kidney cancer space, immunotherapies such as pembrolizumab (Keytruda) and nivolumab (Opdivo) plus ipilimumab (Yervoy) have further solidified a role for select patients, according to Sandy Srinivas, MD.¹ Srinivas, who is vice chair of the Prostate Cancer NCCN Guidelines, also noted that PARP inhibitors are of particular interest in the prostate cancer space; in the latest guideline update, olaparib (Lynparza) and rucaparib (Rubraca) were both added as category 1 preferred regimens for patients with BRCA mutations who experienced disease progression on novel hormone therapy and did not receive docetaxel.²

“NCCN guidelines are integral to every practice, not just for providers [as] there are a variety of new drugs that are being approved, but also for our office staff,” Srinivas said in an interview with OncLive®. “For our office staff who are working on obtaining prior authorization, having the approval and having it in the guidelines is integral.”

The Biggest NCCN Revisions in Kidney Cancer:¹

• A T4, M0 pathway was added:
  • Adjuvant pembrolizumab was also added as primary treatment for patients with resectable disease and clear cell histology (category 2A)
• For adjuvant treatment:
  • Pembrolizumab was modified from a category 2A to category 1 recommendation for patients with clear cell histology in the stage II and III pathways
  • Sunitinib (Sutent) was removed for patients with clear cell histology and stage II disease
• For first-line therapy of clear cell histology:
  • Nivolumab plus ipilimumab was moved to preferred regimens from other recommended regimens for patients with favorable-risk disease
  • High-dose IL-2d was removed from useful in certain circumstances for patients with favorable and poor/intermediate risk disease
  • Temsirolimus (Torisel) was removed from useful in certain circumstances for patients with poor/intermediate risk disease
• For subsequent therapy of clear cell histology regardless of receipt of prior immunotherapy:
  • High-dose IL-2d was removed from useful in certain circumstances
  • Temsirolimus was removed from useful in certain circumstances
• For systemic therapy of non-clear cell histology:
  • Lenvatinib (Lenvima) plus pembrolizumab was added under preferred regimens (category 2A)
  • Cabozantinib (Cabometyx) plus nivolumab was moved to preferred regimens from other recommended regimens
  • Several agents were removed from useful in certain circumstances

The Biggest NCCN Revisions in Prostate Cancer:²

Systemic therapy for M1 castration-resistant prostate cancer (CRPC): adenocarcinoma

• For no prior docetaxel/no prior novel hormone therapy:
  • Pembrolizumab was added as useful in certain circumstances (category 2B) for microsatellite instability–high (MSI-H)/ mismatch repair–deficient (dMMR) disease
• For progression on prior docetaxel/no prior novel hormone therapy:
  • Pembrolizumab was added as useful in certain circumstances (category 2B) for MSI-H/dMMR disease
• For progression on prior novel hormone therapy/no prior docetaxel:
  • Olaparib and rucaparib were both added as preferred regimens for patients with BRCA mutations (category 1)
  • Olaparib was modified for HRR mutations other than BRCA1/2 and is noted as useful in certain circumstances
  • Pembrolizumab was added as useful in certain circumstances for MSI-H/dMMR disease
  • Abiraterone, abiraterone plus dexamethasone, and enzalutamide (Xtandi) were removed from other recommended regimens
• For progression on prior docetaxel and a novel hormone therapy:
  • Abiraterone and enzalutamide were removed from other recommended regimens

In the interview, Srinivas detailed updates from 2024 to the NCCN Clinical Practice Guidelines in Oncology for kidney and prostate cancer; for kidney cancer, the NCCN has already released version 2 of the 2025 guidelines. Srinivas is a medical oncologist, professor of medicine, and clinical research group leader for the Urologic Program at Stanford Medicine in Palo Alto, California.

OncLive: What recent NCCN guideline updates have had an immediate influence on how you practice in kidney cancer?

Srinivas: This was a busy year for the kidney cancer [research] groups. I was happy to see that nivolumab plus ipilimumab got updated in the favorable-risk category [recommendation and moved from other recommended regimens to preferred regimens]. Up until now for those with favorable-risk [disease], it’s been the immuno-oncology/TKI combinations that have made it to category 1 but the phase 3 CheckMate 214 study [NCT02231749] with 8-year follow-up data [showed that] the group of patients with favorable-risk disease seem to be deriving a benefit, especially those who respond with a durable response. [Therefore], it was great to see nivolumab plus ipilimumab make it to the favorable-risk [section] for patients with clear cell renal cell carcinoma [RCC].

Second, a big change was [the addition of the] category 1 recommendation for adjuvant pembrolizumab for patients with high-risk kidney cancer post nephrectomy. This is based on data from the phase 3 KEYNOTE-564 study [NCT03142334], which demonstrated an improvement in disease-free survival [with pembrolizumab vs placebo]. More recently, we also saw that there was a benefit in overall survival, so pembrolizumab made it to the guidelines as a category 1 recommendation in the adjuvant setting.

In non-clear cell RCC, there were a few changes that were made. We have been using cabozantinib as a monotherapy, but we also saw that the combination of cabozantinib with nivolumab as well as lenvatinib and pembrolizumab were [added] to the preferred recommendations. This was based on these combinations [yielding] response rates close to 50%. [They] certainly are a great option for our patients with non-clear cell RCC.

What 2024 NCCN guideline updates have had an influence on how you practice in prostate cancer?

I find the genomic risk stratification for patients with more localized disease, especially those who undergo radiation, interesting. How we incorporate genomic testing into our prognostication as well as assessment of duration of therapy is an interesting addition.

One group of drugs that I’d like to highlight are PARP inhibitors, which have been approved as single agents in prostate cancer, but now are also available in combinations. There have been 3 such combinations: abiraterone with olaparib, abiraterone with niraparib, and, more recently, talazoparib with enzalutamide. All 3 combinations are category 1 [recommendations for useful in certain circumstances] in the untreated with novel hormonal therapy and docetaxel [population based on mutational status]; they do make it to the other clinical states in the CRPC space, but with a lesser level of evidence of benefit.

What is key to note for community oncologists who are adapting to recent guideline changes?

It’s a daunting task to keep up with the drug approvals in all of the cancers that community oncologists treat. NCCN guidelines are key where every time there is a new drug that’s approved, or if there is a new indication for an existing drug, the NCCN has been very good about updating the guidelines. For community oncologists who are not seeing a specific disease that often, referring to the guideline updates is key.

Have you faced any challenges integrating updates to the guidelines into your practice?

The biggest challenge that I believe all of us face is the rapidity and the pace at which drugs are being approved. One of the biggest challenges that we and many practices have is that the authorization parties also have a hard time keeping up with the guidelines, so our office staff and others who advocate for patients end up spending a lot of time trying to provide evidence to third party payers about the updated guidelines.

How do you communicate guideline changes to your patients who are receiving treatment?

I don’t believe that’s a normal conversation because our patients rely on us to be current on our guidelines and be their advocates in making recommendations. I’m not sure every day there is a conversation with the patient saying, ‘this is the new guideline’. We are giving patients our recommendations based on what is appropriate for a given patient based on their disease state.

Are there any changes you anticipate coming in 2025 following guideline updates that you’d like to highlight?

I want to highlight a few trials in the prostate space. Within the field of radioligand theranostics, we have lutetium-177 vipivotide tetraxetan [Pluvicto] which is currently approved for patients in the very refractory space. These are patients who have had prior taxanes [and] prior novel hormonal therapy. We await the results [as] there have been 2 large [phase 3] trials, PSMAfore [NCT04689828] and SPLASH [NCT04647526]. These are trials that were [conducted] in the pre-docetaxel, pre-chemotherapy space. Both trials have met their primary end point. We are looking forward to having a regulatory approval so that our patients can get this drug pre-chemotherapy.

[Another] trial that I’m excited about [from which] we saw some big updates for this year was the phase 3 PEACE III trial [NCT02194842], which looked at the combination of enzalutamide plus radium-223 dichloride in the first-line CRPC space. This is for patients who have never had prior exposure to a novel hormonal therapy. If such patients exist, considering the combination of enzalutamide with radium-223 dichloride [Xofigo] is a very reasonable option. We’re looking forward to these updates in the near future.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 2.2025. Accessed November 13, 2024. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdfNCCN.
2. Clinical Practice Guidelines in Oncology. Prostate cancer, version 4.2024. Accessed November 13, 2024. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf