Ryan McDonald

Combination therapy with the PARP inhibitor rucaparib (Rubraca) and the immunotherapy nivolumab (Opdivo) demonstrated clinical activity in patients with homologous recombination deficiency–positive metastatic castration-resistant prostate cancer (mCRPC) who had no prior chemotherapy, according to findings shared during the 2021 ESMO Congress.

The findings from the CheckMate 9KD trial also showed noteworthy activity in individuals whose tumors harbored 

mutations. However, as study author Daniel P. Petrylak, MD, professor of medicine and urology at Yale School of Medicine and co-director of the Cancer Signaling Networks Research Program at Yale Cancer Center in New Haven, Connecticut, noted in his presentation of data, there was limited clinical activity with the combination in patients with HRD-negative tumors.

Among all cohorts of the phase 2 CheckMate 9KD trial (NCT03338790), patients had to have mCRPC, documented disease progression, an ECOG performance status of 0-1, available tumor tissue for HRD testing and no prior treatment with drugs that targeted T-cell co-stimulation or immune checkpoint pathways.

Here, Petrylak presented data from the final analysis of cohort A2 — which comprised 71 patients (median age, 73 years; range, 51-87 years) who had received 1 to 2 prior new hormonal therapies in the pre-chemotherapy setting. Patients in this cohort also did not receive any prior treatments with PARP inhibitors. Additionally, patients who made up the study population were ineligible for (or refused) immediate chemotherapy.

Nivolumab was administered at a 480-mg dose every 4 weeks (Q4W) and rucaparib was given at a 600-mg dose twice per day (BID). Treatment was given until a patient’s disease progressed or unacceptable toxicity was reached. Of note, nivolumab dosing was limited to a maximum of 2 years.

The primary endpoints assessed in this cohort were overall response rate (ORR) and PSA response rate (PSA-RR). Additional secondary endpoints included overall survival (OS), time to and duration of objective response, time to PSA progression, safety and radiographic progression-free survival (rPFS).

More than half (57.7%) of the patient population in the cohort had an ECOG performance status of 1. All other patients had an ECOG status of 0. HRD status was almost evenly split in the cohort:

47.9% of patients had HRD-positive tumors;

50.7% of patients had HRD-negative tumors, and

1.4% of patients had an undetermined HRD status.

In terms of prior treatment with new hormonal therapies, 60.6% of patients had received abiraterone monotherapy, 23.9% received enzalutamide monotherapy and 14.1% received a combination of those two.

The median treatment duration of nivolumab was 4.6 months and 5.5 months for rucaparib.

After a median follow-up of 17.5 months, the ORR among all evaluable patients (n = 39) was 15.4% (95% CI, 5.9-30.5). Confirmed ORR among the 20 patients with HRD-positive tumors was 25% (95% CI, 8.7-49.1). Moreover, the 9 patients whose disease harbored 

-positive mutations achieved an ORR of 33.3% (95% CI, 7.5-70.1). However, ORR was unfavorable in the 19 patients who had HRD-negative or not evaluable tumors (5.3%; 95% CI, 0.1-26.0).

The trend of noteworthy clinical activity in patients with HRD-positive tumors and 

-positive mutations continued in confirmed PSA-RRs. Among 66 evaluable patients, confirmed PSA-RR reached 27.3% (95% CI, 17.0-39.6). The confirmed PSA-RR rate among patients with HRD-positive tumors (n = 31) was 41.9% (95% CI, 24.5-60.9). And the 13 patients with 

-positive mutations achieved a confirmed PSA-RR of 84.6% (95% CI, 54.6-98.1).

Petrylak also noted that the results showed survival outcomes favored patients with HRD-positive tumors. Among the overall population (n = 71), the median rPFS was 8.1 months (95% CI, 5.6-10.9). The median rPFS in those with HRD-negative tumors (n = 37) was 5.6 months (95% CI, 3.7-9.1) compared to 10.9 months (95% CI, 6.7-12.0) in those with HRD-positive tumors (n = 34).

Treatment with the combination was also associated with favorable OS results. The median OS among all patients was 20.2 months (95% CI, 14.1-22.8). The median OS in the 34 patients with HRD-positive tumors was 22.7 months (95% CI, 14.1 months-NE). Patients in the HRD-negative group (n = 37) had the least favorable median OS at 19.0 months (95% CI, 8.2-22.1).

Most of the study participants (n = 64) experienced a treatment-related adverse event (TRAE) of any grade. And, approximately half (n = 36) experienced a TRAE that was classified as grade 3 or 4.

Petrylak noted that the most common TRAEs included nausea, anemia, fatigue and increased liver enzymes. He also highlighted that there were no study deaths related to treatment.

Although the results showed favorable outcomes associated with the use of nivolumab and rucaparib in these patients, Petrylak expressed that more research is needed.

“Longer follow-up is needed to better characterize the clinical benefits of adding nivolumab to rucaparib for patients with HRD-positive, chemotherapy-naïve metastatic castration resistant prostate cancer,” he concluded.

1. Petrylak DP, et al. CheckMate 9KD cohort A2 final analysis: Nivolumab (NIVO) + rucaparib for chemotherapy (CT)-naïve metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2021 ESMO Annual Congress. September 16-21, 2021. Abstract 579MO.

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There was limited clinical activity with the combination in patients with HRD-negative tumors. 

Rucaparib/nivolumab combo shows clinical activity in HRD-positive mCRPC

Findings from the phase 3 KEYNOTE-581/CLEAR trial (Study 307) showed that frontline therapy with pembrolizumab (Keytruda) plus lenvatinib (Lenvima) reduced the risk of death by 34% versus sunitinib (Sutent) in patients with advanced renal cell carcinoma (RCC).

The combination of the anti–PD-1 immunotherapy and the multikinase inhibitor also improved progression-free survival (PFS) and response compared with sunitinib. The results of the trial, which were presented at the 2021 Genitourinary Cancers Symposium and simultaneously published in the 

, also showed that combining lenvatinib with the mTOR inhibitor everolimus (Afinitor) improved PFS and objective response rate (ORR) but not OS versus sunitinib in this setting.

Previously, single-agent lenvatinib and pembrolizumab have been shown to be effective in treating RCC. The combination of lenvatinib and everolimus has also been shown to induce longer PFS than single-agent everolimus as a second-line treatment option. And, as Robert J. Motzer, MD, noted, results of a recent phase 1b/2 study of lenvatinib plus pembrolizumab showed anti-tumor activity in previously treated patients with RCC.

As a result, researchers aimed to assess the safety and efficacy of lenvatinib plus pembrolizumab, as well as lenvatinib plus everolimus, versus sunitinib alone in the first-line treatment of advanced RCC.

Motzer, the Kidney Cancer Section Head, Genitourinary Oncology Service; and Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center, presented the results of the multi-center, open-label trial during the meeting.

Patients were eligible to enroll onto the trial if they were treatment-naïve, had adequate organ function, measurable disease and presented with advanced clear-cell RCC. Patients were then stratified into 2 geographic regions — Western Europe and North America vs. rest of the world — and stratified by favorable, intermediate or poor disease risk.

The trial comprised 1069 patients who were then randomized in a 1:1:1 fashion to receive lenvatinib 20 mg oral QD plus pembrolizumab 200 mg IV Q3W (n = 355), lenvatinib 18 mg oral QD plus everolimus 5 mg oral QD (n = 357), or sunitinib 50 mg oral QD for 4 weeks on and 2 weeks off (n = 357).

PFS by IRC per RECIST v1.1 was the primary endpoint, and secondary endpoints included OS, ORR by IRC per RECIST v1.1, safety and health-related quality of life (HRQoL).

The median PFS with lenvatinib and pembrolizumab was 23.9 months (95% CI, 20.8-27.7) compared to 9.2 months (95% CI, 6-11) with single-agent sunitinib (HR, 0.39; 95% CI, 0.32-0.49; 

< .001). The lenvatinib plus everolimus treatment arm achieved a median PFS of 14.7 months (95% CI, 11.1-16.7) compared to the 9.2 months in the sunitinib arm (HR, 0.65; 95% CI, 0.53-0.8; 

The PFS benefit extended across all patient subgroups in both the lenvatinib and pembrolizumab and lenvatinib and everolimus treatment arms.

A median OS was not reached in any of the three treatment arms; however, the data indicated the endpoint was significantly longer in the lenvatinib and pembrolizumab arm compared to the sunitinib arm (HR, 0.66; 95% CI, 0.49-0.88; 

= .005). Motzer noted that there was no observed OS benefit in the lenvatinib and everolimus treatment arm over sunitinib alone (HR, 1.15; 95% CI, 0.88-1.5; 

ORR was higher in both the lenvatinib plus pembrolizumab (71%; 95% CI, 66.3-75.7) and lenvatinib plus everolimus (53.5%; 95% CI, 48.3-58.7) treatment arms compared to sunitinib (36.1%; 95% CI, 31.2-41.1). Of note, Motzer mentioned the “high complete response rate” of 16.1% in the lenvatinib plus pembrolizumab arm.

Patients in the lenvatinib plus pembrolizumab arm achieved the longest median DOR at 25.8 months (95% CI, 22.1-27.9), compared to 16.6 months (95% CI, 14.6-20.6) in the lenvatinib plus everolimus arm and 14.6 months (95% CI, 9.4-16.7) in the sunitinib arm.

Nearly all patients in each treatment arm – lenvatinib plus pembrolizumab (96.9%), lenvatinib plus everolimus (97.7%) and sunitinib (92.1%) – experienced any treatment-related adverse event (TRAE). Patients in the lenvatinib plus pembrolizumab (67.3%) and lenvatinib plus everolimus (69.3%) treatment arms were more likely than the sunitinib arm (49.7%) to experience TRAEs that led to dose reductions. Of note, Motzer highlighted that the number of patients needing to have lenvatinib discontinued in either treatment arm was 18.5% and 16.1%, respectively. Moreover, the discontinuation rate of both drugs in the lenvatinib plus pembrolizumab arm was 9.7%.

Motzer noted the safety profiles of both combinations were consistent with each drugs’ known safety profile and were manageable as needed for dose modifications.

“These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC,” he concluded.

1. Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). 

. 2021; 39(suppl6):269. doi: 10.1200/JCO.2021.39.6_suppl.269.

2. Motzer RJ, Alekseev B, Rha S.-Y., et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Published online February 13, 2021. 

The combination of the anti–PD-1 immunotherapy and the multikinase inhibitor also extended progression-free survival in the phase 3 KEYNOTE-581/CLEAR trial (Study 307).

Ryan McDonald

Articles

Rucaparib/nivolumab combo shows clinical activity in HRD-positive mCRPC

Pembrolizumab plus lenvatinib boosts survival in frontline kidney cancer