The COMBAT trial: use of bipolar androgen therapy to enhance immune checkpoint blockade in the management of metastatic castration-resistant prostate cancer
Editorial Commentary

The COMBAT trial: use of bipolar androgen therapy to enhance immune checkpoint blockade in the management of metastatic castration-resistant prostate cancer

Harshraj Leuva ORCID logo, Benjamin A. Teply

Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA

Correspondence to: Benjamin A. Teply, MD. Division of Hematology/Oncology, Department of Internal Medicine, 986840 Nebraska Medical Center, Omaha, NE 68198-6840, USA. Email: ben.teply@unmc.edu.

Comment on: Markowski MC, Taplin ME, Aggarwal R, et al. Bipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial. Nat Commun 2024;15:14.

Keywords: Bipolar androgen therapy (BAT); immune checkpoint inhibitor (ICI); metastatic castrate resistant prostate cancer (mCRPC)

Received: 29 June 2024; Accepted: 10 October 2024; Published online: 15 November 2024.

doi: 10.21037/actr-24-109

Metastatic prostate cancer is a lethal disease. The addition of novel hormonal therapy/androgen receptor pathway inhibitors (NHT/ARPI) such as abiraterone and enzalutamide to androgen deprivation therapy (ADT) with GnRH agonist/antagonist has improved patient survival (1-4). This is now the standard of care for metastatic hormone-sensitive (mHSPC) and metastatic hormone-resistant prostate cancer (mCRPC). One potential resistance mechanism is that prostate cancer cells adapt to androgen ablation by significantly upregulating the androgen receptor (AR) over time in response to low-androgen conditions (5,6). Preclinical studies have observed that this adaptive AR upregulation creates a therapeutic vulnerability, allowing prostate cancer cells to be eradicated by exposure to supraphysiologic testosterone (7,8). This observation has led to the development of an innovative approach known as bipolar androgen therapy (BAT), which involves rapid cycling between high and low serum testosterone levels through the administration of testosterone and ADT (9). In castrate-resistant prostate cancer, increasing testosterone to supraphysiological levels has been shown to downregulate AR splice variants, inhibit cell cycle progression, and increase genomic rearrangements (8,10-12). Initial clinical studies have noted the safety and efficacy of BAT (13-15). However, the precise role of BAT in the management of advanced prostate cancer remains under investigation.

Immune checkpoint inhibitors (ICIs) have demonstrated limited benefit for patients with mCRPC (16). Notably, three patients with stable microsatellite status and low tumor mutational burden mCRPC exhibited lasting clinical responses to ICI after receiving BAT (17). This observation generated the hypothesis that BAT may result in changes in the immune microenvironment in mCRPC to allow for responses to ICI. The COMBAT trial was designed to formally test the activity of ICI with BAT (18). The COMBAT trial is a phase II multicenter study assessing BAT followed by ICI in mCRPC patients with disease progression after at least one NHT/ARPI, and who have soft tissue tumors suitable for metastatic biopsy at the start of the study. Upon enrollment, all suitable patients continued on ADT and began receiving an intramuscular injection of testosterone cypionate 400 mg every 4 weeks for an initial 12-week period. After this phase, all participants received nivolumab 480 mg intravenously every 4 weeks, while continuing with testosterone cypionate 400 mg intramuscularly every four weeks. Treatment was sustained for at least 12 weeks and continued until either prostate-specific antigen (PSA) progression according to Prostate Cancer Working Group 3 (PCWG3) criteria, clinical or radiographic progression (whichever occurred first), or until side effects became too severe to manage, necessitating the cessation of the drug. Assessments for response to testosterone + nivolumab occurred every 3 months. The primary endpoint was the PSA50 response rate, defined as a reduction of ≥50% in PSA levels from baseline, confirmed by a second measurement taken at least 4 weeks later. Secondary endpoints included objective response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS), PSA progression-free survival (PSA PFS), clinical or radiographic progression-free survival (crPFS), median duration of treatment, and the safety of BAT + nivolumab.

The trial included a total of 45 patients. The median age of the patient was 69 years, with half of patients having Gleason ≥9 disease. 53% were treated with two or more lines of NHT/ARPI, and 44% received prior taxane chemotherapy. The study achieved its primary endpoint, with a confirmed PSA50 response rate of 40% (18 out of 45 patients, P=0.02). It is important to note that 16 of 18 PSA50 responses were achieved before adding nivolumab with BAT alone. Two confirmed PSA50 responses and three objective responses were noted after adding nivolumab.

The median follow-up time for the study was 17.9 months. The median rPFS and median OS were estimated at 5.6 (95% CI: 5.4–6.8) and 24.4 (95% CI: 17.6–31.1) months, respectively. The median clinical or radiographic PFS was 5.6 months, while the median PSA PFS was 4.0 months, and the median treatment duration was 5.6 months.

The study did not identify any additional toxicities for the combination than what is known for BAT and ICI individually. Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 toxicities were noted in 6 (13%) of patients, and no treatment-related deaths were reported.

Before treatment initiation, all patients received a mandatory soft tissue biopsy, followed by a second biopsy after completing three cycles of BAT. Due to insufficient tumor tissue or inadequate RNA yield in some biopsies, only 12 of 45 (27%) patients had suitable paired samples for RNA sequencing. Among these 12 patients, six exhibited a positive response to BAT + nivolumab, while the remaining six did not. Comparative analysis of pre-and-on-treatment paired samples revealed that BAT significantly enhanced gene sets linked to inflammation (such as Allograft Rejection and Interferon Gamma Response) in responders but not non-responders.

In a cohort of 23 patients (51%) with pre- and post-treatment biopsies, the impact of BAT on intratumoral T cell density and its association with clinical response to BAT ± nivolumab was investigated. Prior to treatment, patients who responded to BAT ± nivolumab exhibited significantly higher densities of PD-1+ CD8+ and CD4+ T cells compared to non-responders. While BAT treatment did not significantly alter the overall density of CD8+ or CD4+ T cells, these findings suggest a potential correlation between pretreatment T cell subtype abundance and clinical outcome.

While the COMBAT trial met its primary endpoint of a confirmed PSA50 response rate estimated at 40% (18/45), 89% (16/18) of the responses were due to BAT alone, and it notes 36% (16/45) response to BAT. Numerically these are higher response rates than what was previously indicated in TRANSFORMER or RESTORE trials, being 28% and 30%, respectively. However, it is important to note that this cannot be distinguished statistically due to overlapping 95% confidence intervals and, more importantly, these being different clinical trials (14,19). The population in the COMBAT study was different with regard to metastatic disease distribution. The mandate that subjects were required to have soft tissue disease may have accounted for a difference in response rate. Despite the higher response rate, the rPFS was similar to prior studies of BAT alone. Specifically, the phase II randomized TRANSFORMER study comparing enzalutamide to BAT post-abiraterone progression noted a similar rPFS of 5.7 months with BAT alone. Despite the addition of nivolumab, the median rPFS and median time on treatment on COMBAT were 5.6 months. However, the major difference between the two studies is that the COMBAT study enrolled more advanced patients, with half receiving prior chemotherapy, which was not allowed in either TRANSFORMER or RESTORE.

Responses after the addition of nivolumab in the study were uncommon. The promise of ICI, in part, lies with the possibility of durable responses, or a tail of the curve indicating long-term responses. Unfortunately, this tail was not observed on the survival curves in the COMBAT study. A particular strength of this study was the tissue biopsies to understand the intratumoral changes possibly leading to ICI response. An association between increased infiltrating T-cells in responding subjects and response was noted. While BAT has the apparent ability to produce a more immune “hot” microenvironment in some tumors, more work is required to understand the mechanism, as it was not universally seen.

Currently, BAT is only studied in men with relatively asymptomatic progression. In the COMBAT trial, in addition to only including patients who had sites of disease amenable to biopsy, patients were excluded if they had five or more sites of visceral disease, were on opioid analgesics due to tumor-related pain, or were at risk for urinary obstruction or cord compression. Thus, this would be a significant limitation to its broader applicability (similar to other studies performed with BAT). For example, 41% of patients were reported to have pain progression on the abiraterone arm in the LATITUDE trial (3). Additionally, while one prior chemotherapy was allowed, it had to be at least six months before enrollment. In the future, there is likely to be a subset of patients that will meet the criteria for treatment with BAT, but other future work is required to understand its safety in populations with higher burdens or disease or cancer-related pain.

COMBAT is not the only study seeking to use combination therapy to generate benefit from ICI in prostate cancer. A combination of a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab is also being studied, and phase I trial reported a PSA50 response rate of 56% which is encouraging (20). While these novel combinations have shown early promise, the prior efforts to utilize the synergistic potential of ICI have not had much success, and most phase III clinical trials did not meet their primary endpoints compared to the established standard of care (Table 1) (21-26). Thus, this enthusiasm must be met with caution, and it is likely that only a small subset of unselected patients with prostate cancer currently will benefit from ICI. A retrospective study using US-wide Flatiron Health and Foundation Medicine deidentified genomic database noted that ICIs were more efficacious than taxanes in patients with mRPC whose tumor mutational burden was 10 mt/Mb or higher (27). In the Combat trial, it was noted that those who responded to BAT ± nivolumab had a higher density of the PD-1+ subsets of CD8+ and CD4+ cells in the pretreatment biopsy. Thus, a biomarker-based patient selection is an important strategy to explore for appropriate utilization of ICI in mCRPC. NEPTUNES trial provides one example, where patients are selected to receive nivolumab + ipilimumab if they have a positive immunogenic signature (ImS+) (28). Patients were considered ImS+ if they had at least two of the following characteristics: a deficiency in mismatch repair (MMR) as determined by immunohistochemistry, a deficiency in DNA damage repair (DDR) detected through targeted exome sequencing, and a high level of tumor-infiltrating lymphocytes identified using multiplexed immunohistochemistry. ICI remains experimental for the vast majority of CRPC patients. COMBAT moves the prostate cancer field forward in its efforts to produce durable immunotherapy responses in this immunologically cold tumor. However, it is not the end of the war.

Table 1

Phase III studies using ICI combinations in metastatic prostate cancer

Clinical trial, phase Prostate cancer setting Immunotherapy combination* Primary endpoints Results Conclusions
Keynote-921, phase III randomized 2nd-line (post NHT) mCRPC Pembrolizumab + docetaxel vs. docetaxel alone Dual primary endpoint—rPFS and OS Did not meet either primary endpoint of rPFS (HR, 0.85; 95% CI: 0.71–1.01; P=0.0035) or OS (HR, 0.92; 95% CI: 0.78–1.09; P=0.167) No benefit of combination noted
Keynote-991, phase III randomized 1st-line mCSPC Pembrolizumab + enzalutamide vs. enzalutamide alone Dual primary endpoint—rPFS and OS Did not meet primary endpoint of rPFS. HR, 1.20; 95% CI: 0.96−1.49 The study was stopped for futility at the first prespecified interim analysis
Keylynk-010, phase III randomized 3rd-line (post NHT and chemotherapy) mCRPC Pembrolizumab + olaparib vs. 2nd NHT Dual primary endpoint—rPFS and OS Did not meet either primary endpoint of rPFS (HR, 1.02; 95% CI: 0.82–1.25; P=0.55) or OS (HR, 0.94; 95% CI: 0.77–1.14; P=0.26) The study was stopped for futility
Imbassador-250, phase III randomized 3rd-line (post abiraterone and chemotherapy) mCRPC Atezolizumab + enzalutamide vs. enzalutamide alone OS Did not meet the primary endpoint of OS. Stratified HR, 1.12; 95% CI: 0.91–1.37; P=0.28 No benefit for combination noted in primary and secondary end points including response rates, stable disease, progressive disease, duration of response, and prostate-specific antigen response
Contact-02, phase III randomized 2nd line (post NHT) mCRPC with measurable extrapelvic nodal or visceral disease +/− bone disease Atezolizumab + cabozantinib vs. 2nd NHT Dual primary endpoint—rPFS and OS Median rPFS endpooint met: C + A vs. ctrl, 6.3 vs. 4.2 months; HR, 0.65; 95% CI: 0.50–0.84; P=0.0007 Improved rPFS, OS data immature. Grade 3 side effects noted to be 48% in C + A compared to 23% on ctrl
Checkmate-7DX, phase III randomized 2nd line (post NHT) mCRPC Nivolumab + docetaxel vs. docetaxel alone Dual primary endpoint—rPFS and OS Full results yet to be announced, did not meet primary endpoints Did not meet the primary endpoints of rPFS at final analysis, or OS at an interim analysis, and its data-monitoring committee recommended that it be discontinued

*, all patients continue to receive ADT. ADT, androgen deprivation therapy; ICI, immune check point inhibitor; mCSPC, metastatic castrate sensitive prostate cancer; mCRPC, metastatic castrate resistant prostate cancer; NHT, novel hormonal therapy; OS, overall survival; HR, hazard ratio; CI, confidence interval; rPFS, radiographic progression free survival.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-109/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-109/coif). H.L. has received support to institution from Robert Winn Career Development Award. B.A.T. has received consulting fees to individual from Exelixis, Eli Lilly, Sanofi, Seagen, and served on scientific review committee for Pfizer. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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doi: 10.21037/actr-24-109
Cite this article as: Leuva H, Teply BA. The COMBAT trial: use of bipolar androgen therapy to enhance immune checkpoint blockade in the management of metastatic castration-resistant prostate cancer. AME Clin Trials Rev 2024;2:105.

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