Combination Regimens Expand RCC and Prostate Cancer Treatment Armamentariums

Although immunotherapy has no further role after first-line progression for patients with renal cell carcinoma (RCC), TKIs and VEGF inhibitors produce durable responses in this patient population, according to Manojkumar Bupathi, MD, MS. Further, for patients with homologous recombination repair (HRR)–mutated prostate cancer, PARP inhibitor–based combinations provide treatment options beyond chemotherapy alone.

“The second-line [setting for patients with] RCC is changing rapidly. [Several second-line treatment decisions] come down to what you’re using in the first line,” Bupathi said in an interview following an OncLive® Institutional Perspectives in Cancer webinar on genitourinary cancers, which he chaired.

In the interview, Bupathi, a medical oncologist at Rocky Mountain Cancer Centers in Littleton, Colorado, highlighted key points that were presented at the meeting, including the evolving standards of care in first- and second-line RCC; the role of PARP inhibitors in prostate cancer; and the potential uses for next-generation hormonal agents (NHAs) plus androgen deprivation therapy (ADT) in frontline metastatic hormone-sensitive prostate cancer (mHSPC).

In the phase 3 LITESPARK-005 trial (NCT04195750), patients with previously treated advanced clear cell RCC (ccRCC) who received belzutifan (Welireg; n = 374) achieved a median progression-free survival of 5.6 months (95% CI, 3.8-6.5) vs 5.6 months (95% CI, 4.8-5.8) in those who received everolimus (Afinitor; n = 372; HR, 0.74; 95% CI, 0.63-0.88). The median overall survival (OS) was 21.4 months (95% CI, 18.2-24.3) with belzutifan vs 18.1 months (95% CI, 15.8-21.8) with everolimus (HR, 0.88; 95% CI, 0.73-1.07; P = .099).¹ These findings supported the December 2023 FDA approval of belzutifan for patients with advanced RCC who received a prior PD-1/PD-L1 inhibitor and VEGF TKI.²

Regarding prostate cancer, the phase 3 PROpel trial (NCT03732820) evaluated the PARP inhibitor olaparib (Lynparza) plus the NHA abiraterone acetate (Zytiga) vs placebo plus abiraterone acetate in patients with metastatic castration-resistant prostate cancer. Patients in the olaparib arm (n = 399) achieved a median OS of 42.1 months (95% CI, 38.4-not reached) vs 34.7 months (95% CI, 31.0-39.3) in the placebo arm (n = 397; HR, 0.81; 95% CI, 0.67-1.00; P = .054)._³

OncLive: How have combination regimens influenced the first-line RCC treatment paradigm per the presentation by Benjamin Garmezy, MD, of Sarah Cannon Research Institute in Nashville, Tennessee?

Bupathi: In frontline RCC, long-term survival data have been presented and are probably some of the key findings we’ve seen. You can use any immune-oncology [IO]/TKI combination. Picking 1 regimen and perfecting its use is probably one of the most important takeaways. We’ve seen responses in patients with both intermediate- and favorable-risk [disease], as well as patients with poor-risk disease. We’ve seen some durability in responses with combination therapies as well.

Elaine Lam, MD, of the UCHealth Tony Grampsas Urologic Cancer Care Clinic –– Anschutz Medical Campus in Aurora, Colorado, spotlighted key updates in the second-line management of metastatic ccRCC. What does the future look like for the treatment of patients in this population?

In the second line, we’ve seen exciting data from LITESPARK-005, which used belzutifan in the second line and beyond [in patients with ccRCC]. [Belzutifan has] a different therapeutic mechanism compared with that of standard VEGF inhibitors.

[Other insights] we learned from the 2023 ASCO Annual Meeting [surrounded] the use of continuing immunotherapy [after progression on immunotherapy]. [The data from the phase 3] CONTACT-03 trial [NCT04338269] were presented, which showed that there’s no role for continuing immunotherapy [upon] first-line progression. Other [upcoming] data [surround] tivozanib [Fotivda] plus nivolumab [Opdivo] as a second-line therapy. Those data are not yet out, but that combination may be another option that could change how therapy will evolve for patients who progress on first-line immunotherapy.

Mike Lattanzi, MD, of Texas Oncology –– Austin Central, discussed PARP inhibitors in prostate cancer. How might PARP inhibitor–based combinations revolutionize the prostate cancer treatment paradigm?

This is an evolving topic. In prostate cancer, data now show that for first-line castration-resistant patients with HRR alterations, the combination of a PARP inhibitor plus NHA seems to be more active than just switching NHAs or going to chemotherapy. You may have alternative options, as opposed to just going right to systemic chemotherapy.

There’s activity in patients who have alterations in HRR in general, but then the combinations of talazoparib [Talzenna] plus enzalutamide [Xtandi] or abiraterone plus olaparib seem to be evolving now. Those seem to be good first-line options in castration-resistant prostate cancer.

Elizabeth Kessler, MD, of the UCHealth Tony Grampsas Urologic Cancer Care Clinic –– Anschutz Medical Campus, highlighted recent advances in mHSPC. What triplet therapies are on the horizon for this patient population?

Dr Kessler discussed the use of triplet therapy as first-line therapy. Sometimes we think doing more is better, [such as] using a combination of chemotherapy with NHA plus ADT as the first-line combination therapy, based on [findings from] the phase 3 ARASENS [NCT02799602] and PEACE1 [NCT01957436] trials. Evolving [research is] investigating using lutetium Lu 177 vipivotide tetraxetan [Pluvicto] in combination with NHA plus ADT. Those data have not yet been presented but are forthcoming. [Overall], Dr Kessler talked about the evolution of triplet therapy in first-line HSPC.

References

1. Albiges L, Rini BI, Peltola K, et al. Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): randomized open-label phase III LITESPARK-005 study. Ann Oncol. 2023;34(suppl 2):1329-1330. doi:10.1016/j.annonc.2023.10.090
2. FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed December 20, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma?utm_medium=email&utm_source=govdelivery
3. Saad F, Clarke NW, Oya M, et al. Olaparib plus abiraterone versus placebo plus abiraterone in metastatic castration-resistant prostate cancer (PROpel): final prespecified overall survival results of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24(10):1094-1108. doi:10.1016/S1470-2045(23)00382-0