Cabozantinib Plus Atezolizumab Fails to Improve OS Over Subsequent Novel Hormonal Therapy in mCRPC

Neeraj Agarwal, MD, FASCO

Cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) did not demonstrate a statistically significant overall survival (OS) benefit over treatment with a second novel hormonal therapy (NHT) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed on a prior NHT, despite previously meeting its other coprimary end point of improved progression-free survival (PFS), according to findings from the phase 3 CONTACT-02 study (NCT04446117) presented at the 2024 ESMO Congress.¹

Results from the final OS analysis revealed that, at a median follow-up of 24 months (range, 9.8-42.0), cabozantinib plus atezolizumab reduced the risk of death by 11% (HR, 0.8; 95% CI, 0.72–1.10, P = .30) in the intention-to-treat (ITT) population (n = 289). The median OS with the combination was 14.8 months (n = 253; 95% CI, 13.4-16.7) vs 15 months (n = 254; 95% CI, 13.0-18.5) with the second NHT (n = 286).

However, subgroup analyses revealed a trend in favor of the cabozantinib combination for patients with liver metastases (n = 132) and bone metastases (n = 446), in which the regimen reduced the risk of death by approximately 32% (HR, 0.68; 95% CI, 0.47–1.00; P = .051) and 21% (HR, 0.79; 95% CI, 0.63–1.00; P = .046), respectively. The median OS for patients with liver metastases was 12.2 months (95% CI, 8.8-13.8) with the combination (n = 67) and 7.1 months (95 % CI, 5.3-10.4) with a second NHT (n = 65). For patients with liver metastases, the median OS was 13.8 (95% CI, 11.9-16.3) and 11.6 months (95% CI, 10.5-14.1) for these respective arms (n = 229; n = 217).

“OS, the second primary end point, favored cabozantinib plus atezolizumab, but did not achieve statistical significance. [However], a strong survival advantage was seen in patients with liver metastasis whose disease may be evolving to an androgen receptor–indifferentiated phenotype. Cabozantinib plus atezolizumab, a treatment option with a novel mechanism of action, may [therefore] be useful for selected patients with mCRPC who have progressed on an NHT,” lead study author Neeraj Agarwal, MD, a professor of medicine and the Presidential Endowed Chair of Cancer Research at the University of Utah, Huntsman Cancer Institute, in Salt Lake City, stated in a presentation of the data.

Results from the primary analysis of CONTACT-02, which were previously presented at the 2024 Genitourinary Cancers Symposium, showed that cabozantinib plus atezolizumab generated a statistically significant and clinically meaningful improvement in PFS, meeting one of the trial’s coprimary end points. At a median follow-up of 14.3 months (range, 5.0-28.4), in the PFS ITT population, the median PFS per blinded independent review committee (BIRC) assessment was 6.3 months (95% CI, 6.2-8.8) vs 4.2 months (95% CI, 3.7-5.7) in the cabozantinib vs NHT arms, respectively, (HR, 0.65; 95% CI, 0.50-0.84; P = .0007).²

The PFS benefit with cabozantinib plus atezolizumab was notable in patients with liver metastases, at a median PFS of 6.2 months (95% CI, 4.0-9.1) with the combination vs 2.1 months (95% CI, 2.0-2.3) with the second NHT (HR, 0.43; 95% CI, 0.27-0.68). For patients with bone metastases, the median PFS was 6.3 months (95% CI, 6.0-8.6) vs 4.1 (95% CI, 2.8-5.7) in the respective arms (HR, 0.67; 95% CI, 0.50-0.88).^1,2

Overview of CONTACT-02

CONTACT-02 enrolled patients at least 18 years of age with mCRPC and histologically confirmed adenocarcinoma who experienced disease progression following 1 prior NHT and displayed either prostate-specific antigen (PSA) or soft-tissue progression. Notably, rapid progression on the first NHT was not required, and prior docetaxel for locally advanced or metastatic castration-sensitive prostate cancer (mCSPC) was allowed. An ECOG performance status (PS) of 0 or 1 was required. Patients were stratified by liver metastasis, prior receipt of docetaxel, and disease stage for which first NHT was given.

Upon enrollment, patients were randomly assigned 1:1 to receive either 40 mg of oral cabozantinib per day alongside 1200 mg of intravenous atezolizumab every 3 weeks or a second NHT. NHT options included 1000 mg of oral abiraterone acetate (Zytiga) daily plus 5 mg of oral prednisone twice daily or 160 mg of oral enzalutamide (Xtandi) per day. Treatment continued until loss of clinical benefit or intolerable toxicity. Tumor assessments were performed at baseline, every 9 weeks for 28 weeks, and ever 12 weeks thereafter.

The study’s primary end points were PFS in the PFS ITT population per RECIST 1.1 criteria by BIRC in the first 400 randomly assigned patients, and OS in the ITT population. Overall response rate per RECIST 1.1 by BIRC served as a secondary end point. Other key end points included PFS in the ITT population; radiographic PFS per PCWG3 by BIRC; PSA response rate, time to PSA progression, symptomatic skeletal event, chemotherapy or pain progression; and safety. 

A total of 989 patients were screened, 575 of which were enrolled onto the study. Notably, the study population had a high representation of poor prognostic features. The median age was 71 years in both the cabozantinib combination arm (range, 48-91) and the comparator arm (range, 45-89). Most patients came from Europe (49%, cabozantinib arm; 48%, NHT arm) followed by Latin America (22%; 22%) Asia Pacific (19%; 20%) and North America (10%; 11%). In the cabozantinib arm, 52% of patients had an ECOG PS of 1 compared with 47% in the second NHT arm. The majority of patients across both arms had a Gleason Score of 8 or greater at diagnosis (60%; 59%) and a diagnosis of de novo metastatic disease per investigator (52%; 51%). The median PSA was 31.4 µg/L (IQR, 7.9-96.0) and 26.9 µg/L (IQR, 6.9-102.2) in the cabozantinib and NHT arms, respectively.

Sites of extrapelvic measurable metastases included lymph node metastases (75%; 74%) visceral metastases (38%; 41%) and bone metastases (79%; 76%). In both arms, liver metastases were observed in 23% of patients and 22% had received prior docetaxel for mCSPC. Disease states for which first NHT was given included mCSPC (20%; 19%), M0 CRPC (7%; 6%) and mCRPC (74%; 74%). The median duration on first NHT was 12.4 months (range, 0.4-81.0) in the cabozantinib combination arm vs 11.9 months (range, 0.1-78.9) in the second NHT arm.

Additional Efficacy and Safety Data

Further efficacy assessment of the combination (n = 253) and the second NHT (n = 254) arms showed that the time of chemotherapy was 19.6 months (95% CI, 16.2-26.9) vs 10.4 (95% CI, 8.3-15.3), respectively (HR, 0.59; 95% CI, 0.45-0.77). The median time to deterioration of EORTC QLQ-C30 Global Health Status was 4.1 months (95% CI, 2.6-4.2) vs 4.2 months (95% CI, 3.0-4.3) in these respective arms (HR, 1.19; 95% CI, 0.94-1.51). The time to symptomatic skeletal events was 24.0 months (95% CI, 16.3-not evaluable [NE]) vs 17.3 months (95% CI, 13.2-NE), respectively (HR, 0.73; 95% CI, 0.44-1.20).

At the data cutoff, a total of 22 in the combination arm and 20 patients in the NHT arm were continuing on study treatment. Reasons for treatment discontinuation included progressive disease (discontinued cabozantinib, n = 132; atezolizumab, n = 141; all study treatment in NHT arm, n = 158), adverse effects (AEs; n = 79; n = 67; n = 43), patient withdrawal (n = 24; n = 22; n = 22) and other reasons (n = 32; n = 38; n = 43).

The median duration of exposure to study treatment was 6.3 months (range, 0.4-38.5) in the cabozantinib arm vs 4.2 months (range, 0.1-41.5) in the second NHT arm. The median dose intensity relative to the full dose was 83% (range, 21%-100%) for cabozantinib, 83% (range, 20%-100%) for atezolizumab, and 100% (range, 13%-101%) for NHT.

AEs leading to dose reduction of cabozantinib, dose hold, or dose delay of atezolizumab were reported in 49%, 73% and 55% of patients, respectively. AEs leading to dose reductions or holds of the second NHT were observed in 4% and 18% of patients, respectively.

Regarding safety, all safety-evaluable patients in the cabozantinib combination arm (n = 284) experienced any treatment-emergent AE (TEAE) compare with 92% in the second NHT arm (n = 284). Any treatment-related AEs (TRAEs) were reported in 94% and 45% of patients in these respective arms. The frequency of both grade 3/4 TEAEs and TRAEs was higher with the cabozantinib combination (56%; 40%) vs the second NHT (26%; 8%).

Common any-grade TEAEs included diarrhea (48%; 7%), decrease appetite (40%; 15%), fatigue (30%; 20%), anemia (28%; 19%), nausea (28%; 13%), asthenia (28%; 14%), increased aspartate aminotransferase levels (25%; 6%), increase alanine aminotransferase levels (24%; 4%), hypothyroidism (23%; 1%), hypertension (21%; 7%), and stomatitis (20%; 1%). The most notable grade 3/4 TEAEs were diarrhea (5%; 1%), fatigue (6%; 2%), anemia (8%; 6%), and hypertension (8%; 2%).

A total of 132 patients in the combination arm and 149 patients in the NHT arm went on to receive subsequent anticancer systemic therapy. Overall, less patients treated with cabozantinib plus atezolizumab received a taxane as subsequent therapy than those treated with a second NHT (74% vs 87%). However, a greater percentage of this patient population went on to receive subsequent NHT than the second NHT population (33%; 5%).

Dr. Agarwal reports the following disclosures: institutional research funding from Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GlaxoSmithKline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, NewLink Genetics, Novartis,

Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon; and receipt of travel accommodations/expenses from Pfizer.

References

1. Agarwal N, Azad AA, Galceran JC, et al. Cabozantinib (C) plus atezolizumab (A) versus 2nd novel hormonal therapy (NHT) in patients (Pts) with metastatic castration-resistant prostate cancer (mCRPC): Final overall survival (OS) results of the phase III, randomized, CONTACT-02 study. Ann Oncol. 2023;35(suppl 2):1-72.10.1016/annonc/annonc1623
2. Agarwal N, Azad A, Carles J, et al. CONTACT-2: phase 3 study of cabozantinib (C) plus atezolizumab (A) vs second novel hormonal therapy (NHT) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2024;42(suppl 4):18. doi:10.1200/JCO.2024.42.4_suppl.18