How Are Treatment Intensification and Sequencing Reshaping Care in Prostate Cancer and RCC

Androgen deprivation therapy (ADT) was "all we had" for generations in prostate cancer, but management now looks unrecognizable from just a few years ago, Mark Pomerantz, MD, of Dana-Farber Cancer Institute, said during a recent OncLive® Fellows Seminar.¹ Pomerantz and co-moderator Toni Choueiri, MD, also of Dana-Farber Cancer Institute, led fellows through a comprehensive review spanning the full prostate cancer and renal cell carcinoma (RCC) continuums, reflecting the breadth of data trainees are now expected to master.

How is frontline therapy intensifying across the prostate cancer continuum?

In biochemically recurrent, nonmetastatic castration-sensitive disease, data from the phase 3 EMBARK trial (NCT02319837) showed that enzalutamide (Xtandi) plus leuprolide (Lupron; n = 355) reduced the risk of metastasis or death by 58% vs leuprolide alone (n = 358; HR, 0.42; 95% CI, 0.30-0.61; 2-sided P < .001), and enzalutamide monotherapy (n = 355) also improved metastasis-free survival (MFS), though by a smaller margin (HR, 0.63; 95% CI, 0.46-0.87; 2-sided P = .005).²

Pomerantz said he has since adopted enzalutamide monotherapy for select patients who tolerate ADT poorly, calling it “a part of my practice.” In metastatic hormone-sensitive disease. Additionally, doublets such as ADT plus docetaxel or ADT plus an androgen receptor pathway inhibitor (ARPI) and triplets that add darolutamide (Nubeqa) and abiraterone (Zytiga) have improved overall survival (OS).¹

Newer regimens target genomic subsets: the phase 3 AMPLITUDE trial (NCT04497844) showed a radiographic progression-free survival (rPFS) benefit with niraparib (Zejula) plus abiraterone acetate and prednisone vs abiraterone acetate plus prednisone in HRR-deficient metastatic hormone-sensitive disease (HR, 0.52; 95% CI, 0.37-0.62; P < .0001).³ Data from the phase 3 CAPItello-281 trial (NCT04493853) showed a similar signal with capivasertib (Truqap) plus abiraterone that Pomerantz said should be reserved for PTEN loss exceeding 90%.⁴ By contrast, the phase 3 PSMAddition trial (NCT04720157; n = 572 per arm) found that adding upfront lutetium Lu 177 vipivotide tetraxetan (Pluvicto) to ADT plus an ARPI improved rPFS (HR, 0.72; 95% CI, 0.58-0.90; P = .002) without a significant OS benefit (HR, 0.84; 95% CI, 0.63-1.13; P = .125), a result Pomerantz said “doesn’t pass the finger test” for practice-changing data.⁵

What is guiding sequencing decisions in CRPC?

PARP inhibitors are, in Pomerantz’s words, “fantastic” for BRCA2-altered metastatic castration-resistant prostate cancer (mCRPC) and are often sequenced ahead of chemotherapy given their more favorable toxicity profile. Lutetium Lu 177 vipivotide tetraxetan has shown that it can match second-line chemotherapy while being better tolerated and is increasingly used ahead of a second ARPI. Data from the phase 3 PSMAfore trial (NCT04689828) showed outcomes comparable to switching ARPIs in taxane-naive patients, with dry mouth the most persistent adverse effect.⁶ The phase 3 PEACE-3 trial (NCT02194842) added radium-223 (Xofigo) to enzalutamide in mCRPC and improved both rPFS (HR, 0.71; 95% CI, 0.57-0.89) and OS (HR, 0.76; 95% CI, 0.60-0.96) vs enzalutamide alone.⁷

Asked by a fellow whether shorter docetaxel courses could preserve efficacy in triplet regimens, as has been tested in breast cancer, Pomerantz said “no one has systematically looked at that” in prostate cancer, leaving duration an individualized decision. He also cautioned that PSA-based end points can mislead in low-PSA-producing, dedifferentiated tumors such as neuroendocrine prostate cancer, reinforcing that overall survival remains the most reliable measure of benefit.

How are frontline and adjuvant data evolving in ccRCC?

Choueiri opened the RCC review by noting that clear cell histology, a roughly 20-year-old classification, still tracks with distinct molecular alterations that shape prognosis and drug response. In the adjuvant setting, the phase 3 LITESPARK-022 trial (NCT05239728) added belzutifan (Welireg) to pembrolizumab (Keytruda) after nephrectomy, building on the phase 3 KEYNOTE-564 trial (NCT03142334) that established adjuvant pembrolizumab alone; the combination improved disease-free survival (HR, 0.72; 95% CI, 0.59-0.87; P = .0003), though OS data remain immature (HR, 0.78; 95% CI, 0.51-1.19; P = .122) and added toxicity, mainly anemia, was evident.⁸

In metastatic disease, longer follow-up continues to differentiate frontline regimens. Data from the final 9-year analysis of the phase 3 CheckMate 214 trial (NCT02231749) showed durable responses to nivolumab (Opdivo) plus ipilimumab (Yervoy) in IMDC intermediate/poor-risk disease with an overall response rate (ORR) of 42.4% vs 27.5% with sunitinib (Sutent), a median duration of response of 82.8 months vs 19.8 months, respectively.⁹

Five-year updates of the phase 3 KEYNOTE-426 trial (NCT02853331) of pembrolizumab plus axitinib (Inlyta), the phase 3 CheckMate 9ER trial (NCT03141177) of nivolumab plus cabozantinib (Cabometyx), and the phase 3 CLEAR trial (NCT02811861) of lenvatinib plus pembrolizumab each showed higher response rates than nivolumab/ipilimumab, particularly in favorable-risk disease. Choueiri said pembrolizumab-axitinib use has declined, especially in academic centers, in favor of cabozantinib-nivolumab or lenvatinib-pembrolizumab, given their comparatively higher response rates.

He also highlighted the blood-based biomarker KIM-1, which requires only a small blood volume and appears prognostic across treatment lines, as a tool fellows should watch as it moves toward clinical use.

What unmet needs remain in RCC and across the GU continuum?

Non-clear cell RCC remains the area with the least consensus. The phase 2 KEYNOTE-B61 trial (NCT04704219) of pembrolizumab plus lenvatinib produced a 51% ORR across histologies, and the phase 2 SUNNIFORECAST trial (NCT03075423) showed nivolumab plus ipilimumab improved the 12-month OS rate over standard of care, at 78% vs 68%, respectively, with median respective OS values of 33.2 vs 25.2 months.^10-11 Data from phase 3 LITESPARK-011 trial (NCT04586231) showed belzutifan plus lenvatinib improved progression-free survival over cabozantinib after prior immunotherapy (HR, 0.70; 95% CI, 0.59-0.84; P = .00007) without a significant OS benefit (HR, 0.85; 95% CI, 0.68-1.05; P = .061).¹²

Access surfaced as a practical barrier: Choueiri noted belzutifan is among the most expensive oral cancer therapies, at over $30,000 monthly, weighed against incremental benefit for individual patients. Faculty and fellows also returned to how imaging is reshaping disease definitions, since most pivotal trials still classify metastasis by CT and bone scan rather than PSMA-PET. Consistent with the session’s post-event survey, which asked fellows to rate their preparedness on regimen selection, sequencing, biomarker interpretation, and access issues, the discussion underscored that translating a year of dense data into consistent day-to-day practice remains a work in progress.

References

1. Management of Prostate Cancer and Renal Cell Carcinoma: A Review. An OncLive Fellows Seminar. OncLive. June 25, 2026. Accessed July 21, 2026.
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3. Attard G, Agarwal N, Graff JN, et al. Phase 3 AMPLITUDE trial: niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. J Clin Oncol. 2025;43(suppl 17):LBA5006. doi:10.1200/JCO.2025.43.17_suppl.LBA5006
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5. Tagawa ST, Sartor O, Herrmann K, et al. Phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Ann Oncol. 2025;36(suppl 2):S1627-S1628. doi:10.1016/j.annonc.2025.09.101
6. Morris MJ, Hirmand M, Chi KN, et al. PSMAfore: a randomized, phase 3 trial of [177Lu]Lu-PSMA-617 versus a change in androgen receptor pathway inhibitor in taxane-naive patients with metastatic castration-resistant prostate cancer. Lancet. 2024;404(10459):1227-1239. doi:10.1016/S0140-6736(24)01653-2
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8. Choueiri TK, Motzer RJ, Karam JA, et al. Adjuvant pembrolizumab plus belzutifan versus pembrolizumab for clear cell renal cell carcinoma (ccRCC): the randomized phase 3 LITESPARK-022 study. J Clin Oncol. 2026;44(suppl 7):LBA418. doi:10.1200/JCO.2026.44.7_suppl.LBA418
9. Choueiri TK, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: final analysis from the phase 3 CheckMate 214 trial. J Clin Oncol. 2025;43(suppl 16):4505. doi:10.1200/JCO.2025.43.16_suppl.4505
10. Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for advanced non-clear-cell renal cell carcinoma: updated results from the phase 2 KEYNOTE-B61 trial. Eur Urol. 2025;88(6):614-624. doi:10.1016/j.eururo.2025.05.019
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12. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. J Clin Oncol. 2026;44(suppl 7):LBA417. doi:10.1200/JCO.2026.44.7_suppl.LBA417