H&O What is human kallikrein 2 (KLK2), and what makes it a good target in prostate cancer?
MS KLK2 is a membrane-associated protease that is involved in semen liquefaction and regulated by androgen receptor signaling. It is expressed exclusively in the prostate, whereas prostate-specific membrane antigen (PSMA) and the six-transmembrane epithelial antigen of the prostate 1 (STEAP1) are expressed in multiple tissues. The specificity of KLK2 expression allows us to produce KLK2-targeting agents that have a good safety profile. Another advantage of KLK2 is that it is expressed on the surface of prostate cells throughout the entire course of the disease, from early to late stage. KLK2 expression has been shown to persist after multiple lines of therapy, including androgen receptor pathway inhibition and chemotherapy.
H&O What agents are being developed to target KLK2?
MS The agent that is furthest along is the CD3 T-cell engager pasritamig. The multinational, phase 3 KLK2-comPAS study is the first study to compare pasritamig vs placebo in late-line, castration-resistant prostate cancer (NCT07164443). KLK2-comPAS is randomizing patients in a 2:1 ratio to pasritamig plus best supportive care vs placebo plus best supportive care.
H&O What makes pasritamig different from other bispecific antibodies in prostate cancer?
MS As I mentioned earlier, PSMA is more broadly expressed than KLK2, with some expression in the salivary glands, kidneys, and nerve tissue. Because of this off-target effect, bispecific antibodies that target PSMA can cause more on-target, off-tumor side effects than pasritamig would. Pasritamig is less likely than other bispecific antibodies to cause side effects such as cytokine release syndrome (CRS), so it can be administered on an outpatient basis from the first dose. Tocilizumab, which blocks the cytokine interleukin 6, was used at the recommended phase 2 dose. The fact that pasritamig is relatively safe also provides more opportunities to combine it with other medications.
H&O Could you describe the design and results of your study that was published last year?
MS This was a traditional phase 1 dose escalation trial to determine the appropriate dosing of pasritamig for patients with metastatic castration-resistant prostate cancer and whether it should be given subcutaneously or intravenously.1 The trial then added a dose expansion cohort of 174 patients with good performance status, prior androgen-directed therapy and/or chemotherapy, and a prostate-specific antigen (PSA) level of 2 ng/mL. Prior PSMA-directed radioligand therapy was allowed.
We started out with subcutaneous dosing of pasritamig, which caused some skin irritation. We were able to avoid that problem with intravenous dosing, which also reduced the risk of CRS. We used a step-up approach to dosing, which has been proven to be the safest way to give certain medications. Intravenous dosing also allowed us to administer fewer injections, each at a higher dose. The initial intravenous dosing was every 3 weeks, but serendipitously, we had a patient who ended up skipping a dose, and his PSA level started to go down. That observation led to the hypothesis that giving the drug less frequently might be more effective.
We further explored this concept in research that Dr Karen Autio presented at the European Society for Medical Oncology Congress this past fall.2 Preclinical data suggested that a class of T cells exists that can become effector T cells, which are more effective than terminally exhausted T cells at killing tumors. It turns out that if we dose too frequently, we get a higher percentage of terminally exhausted T cells and a lower percentage of effector T cells. As we reduced the frequency of dosing from every 1 week to every 3 weeks and then to every 6 weeks, we saw more transcription factor T-cell factor 1 (TCF1)–positive T cells (effector T cells) and less activation-induced T-cell death.
We concluded that the optimal dosing schedule was 3.5 mg on day 1 and 18 mg on day 8, followed by 300 mg given intravenously every 6 weeks. This approach made for convenient administration and is the dosing schedule that is being used in the phase 3 study. Among the 33 patients who received this regimen, 42% exhibited a decline in PSA of at least 50% (PSA50), and 36% exhibited a confirmed PSA50. The median radiographic progression-free survival (PFS) was approximately 7.9 months. For context, the VISION trial showed a median radiographic PFS of approximately 3.4 months with best supportive care in this late-line population.3
Among the 84 patients who had measurable disease at baseline, the overall response rate was 8% and the median duration of response was 9 months. The rate of CRS was less than 10%, and all cases were grade 1, which represents a fever. This low rate is notable because other bispecific antibodies in development, some of which have been abandoned, have produced CRS rates ranging from more than 30% to 100%. These rates include more than 30% of patients with grade 2 CRS, which requires admission to the hospital. We saw the occasional fever, but no grade 2 or higher events at the recommended phase 2 dose led to discontinuation or dose reduction.
Another interesting study, which Dr Manish Patel presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium, was a phase 1b examination of pasritamig plus docetaxel.4 This study, which used the pasritamig dosing schedule that we developed in our phase 1 study, enrolled 51 patients with metastatic castration-resistant prostate cancer. The confirmed PSA50 rate with the combination was 65%, and the confirmed PSA90 rate was 35%. In taxane-naive patients, the PSA90 rate was 54%. These data support the approach of combining pasritamig and docetaxel, and the phase 3 KLK2-PASenger study is currently looking at this combination (NCT07225946).
H&O Are any other combination treatments with pasritamig being investigated?
MS Right now, researchers are looking at multiple drug combinations with pasritamig as the backbone. For example, a phase 1 trial from Johnson & Johnson is looking at the combination of pasritamig and a CD28 PSMA T-cell engager, with the goal of providing a signal to both the CD3 T-cell receptor and the CD28 T-cell receptor (NCT06095089). Regeneron is also developing a CD28 PSMA T-cell engager called nezastomig (NCT03972657).
A platform trial is using pasritamig as a backbone in combination with other agents, such as antibody-drug conjugates (NCT07082920) and adenosine receptor antagonists (NCT07319871). Coherus Oncology is planning to launch a phase 1b trial with the CCR8 antibody tagmokitug (CHS-114) in combination with pasritamig. A Korean biotechnology company called GI Innovation is launching a phase 1b/2 trial to look at a combination of pasritamig and GI-102, which is a CD80-targeting interleukin 2 derivative.
I could also see pasritamig being used in combination with the radioligand therapy lutetium Lu 177 PSMA-617 (Pluvicto, Novartis).
H&O Is there anything you would like to add?
MS I would like to see more patients in the 2 phase 3 trials that are actively enrolling patients, KLK2-comPAS and KLK2-PASenger. We want to learn more about these agents and which patients are most likely to respond to them.
Disclosures
Dr Stein is on the advisory boards of AstraZeneca, Exelixis, Johnson & Johnson, and Xencor; has received institutional research grants from Advaxis, ArtBio, and Exelixis; has served as a local primary investigator for AstraZeneca, Bicycle Therapeutics, BioNTech RNA Pharmaceuticals GmbH, Duality Bio, OncoC4, Regeneron, and Telix; has served as trial chair for Bristol Myers Squibb and GI Innovation; has served as a steering committee member for Johnson & Johnson; has served as a coordinating primary investigator for Xencor; and has stocks/shares in Rafael Pharmaceuticals.
References
1. Stein MN, Vinceneux A, Robbrecht D, et al. Pasritamig, a first-in-class, bispecific T-cell engager targeting human kallikrein 2, in metastatic castration-resistant prostate cancer: a phase I study. J Clin Oncol. 2025;43(22):2515-2526.
2. Autio K, Schweizer M, Shotts KM, et al. Translational analyses of T cell phenotypes and their association with clinical efficacy in the first-in-human (FIH) trial of JNJ-78278343 (pasritamig) in metastatic castration-resistant prostate cancer (mCRPC) [ESMO abstract 2385MO]. Ann Oncol. 2025;36(suppl 2).
3. Sartor O, de Bono J, Chi KN, et al; VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103.
4. Patel MR, Pachynski RK, Sandhu S, et al. Safety and efficacy of pasritamig (PAS) + docetaxel (DOCE) in participants with metastatic castration-resistant prostate cancer (mcrPc): initial results of a phase 1b study [ASCO GU abstract 171]. J Clin Oncol. 2026;44(7)(suppl).