ADCs, Novel Targets Represent Next Wave of Treatment Advances in mCRPC

Matthew Dallos , MD

Patients with metastatic castration-resistant prostate cancer (mCRPC) have traditionally been burdened by a poor outlook; however, emerging therapeutic targets and novel agents directed at them are poised to affect change in this patient population, according to Matthew Dallos , MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, who presented on the topic during the 16th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies.¹

“I think of [mCRPC treatment] in 2 broad buckets: we have agents that target the tumor, and then we have agents that target the tumor microenvironment,” Dallos said. “There’s a number of ways you can go about doing that. You want a target that has tumor cells specificity [and] ideally target something that’s an oncogenic driver. There’s a number of interesting ways that you can deliver a payload.”

ADCs

Dallos primarily talked through data concerning novel agents in development for patients with mCRPC, first focusing on antibody-drug conjugates (ADCs), namely those targeting prostate-specific membrane antigen (PSMA), B7-H3, Trop-2, and CD46. He noted that PSMA is an excellent prostate cancer–specific target because it is present in approximately 90% to 95% of prostate tumors and can be imaged with a PSMA PET scan.¹

An agent in this vein known simply as PSMA ADC was evaluated in a phase 2 study (NCT01695044). The open-label, single arm phase 2 study enrolled patients with mCRPC who had progressed after prior treatment with abiraterone acetate (Zytiga) and/or enzalutamide (Xtandi), were previously treated with a taxane, and had an ECOG performance status of 2 or less. Patients who underwent more than 2 prior cytotoxic chemotherapies were excluded.²

The trial enrolled 84 chemotherapy-experienced patients and 35 chemotherapy-naïve patients; a total of 113 patients were treated with PSMA ADC. Prostate-specific antigen (PSA) declines of at least 50% (PSA50) were observed in 14% and 21% of all treated and chemotherapy-naïve patients, respectively. Circulating tumor cells declined at least 50% in 78% and 89% of patients, respectively. Dallos noted this represented modest activity.²

In terms of safety, common treatment-related adverse effects (TRAEs) in the chemotherapy-naïve population included neutropenia (31.4%), peripheral neuropathy (8.6%), and decreased electrolytes (14.3%). Overall, 62% of patients discontinued treatment before the fifth cycle; 40% of discontinuations were due to progression and 31% were due to toxicity. The toxicity with the agent is significant with modest activity Dallos concluded.²

“The main toxicity was related to sepsis and neutropenia but also peripheral neuropathy,” Dallos said. “There’s a number of other PSMA ADCs that are in earlier development. [This is] the next generation of these approaches. This one was really one of the first in this space because in prostate [cancer], we have a good target.”

Dallos moved on to discuss another therapeutic target in mCRPC, B7-H3, which has been associated with recurrence and poor outcomes. Although the function of this cell surface immunomodulatory glycoprotein is poorly understood, more than 90% of mCRPCs express it in the membrane. Additionally, there is relatively little B7-H3 expression in normal tissues.³

The B7-H–-directed ADC MGC018 is being examined in a phase 1 study (NCT03729596). The study enrolled patients with solid tumors, including 40 patients with mCRPC. Patients received MGC018 at a dose of 3.0 mg/kg intravenously every 3 weeks. The primary end point was safety and tolerability.⁴

Among 16 efficacy-evaluable patients in the mCRPC cohort, the overall response rate (ORR) was 25%. Moreover, 10 patients with mCRPC experienced reductions in target lesion sums from baseline. Cytopenia, gastrointestinal toxicity, hand-foot syndrome, and pleural effusion were notable TRAEs, although they were mostly low grade. The ongoing phase 2/3 TAMARACK study (NCT05551117) is further examining MGC018 and comparing it with androgen receptor axis-targeted therapy exclusively in patients with mCRPC.⁴

Another investigational B7-H3–directed ADC Dallos highlighted was DS-7300. The agent, which contains a topoisomerase I inhibitor payload, is under evaluation in patients with solid tumors in a phase 1 trial (NCT04145622). The trial enrolled a cohort of 54 patients with mCRPC as part of the dose-escalation and dose-expansion phases. The cohort was heavily pretreated, with a median of 5 prior lines of therapy.⁵

Patients who received DS-7300 experienced an ORR of 33% (95% CI, 21%-47%), including 15 confirmed partial responses. At a median follow-up of 9.3 months (95% CI, 7.5-10.6), the median duration of response (DOR) was 4.4 months (95% CI, 2.7-not reached [NR]). Notable toxicities included interstitial lung disease, gastrointestinal toxicities, and cytopenia, according to Dallos.⁵

Dallos then touched on the potential of Trop-2 as a therapeutic target in mCRPC. The Trop-2-directed ADC sacituzumab govitecan-hziy (Trodelvy) has displayed efficacy in breast cancer and metastatic urothelial carcinoma. High Trop-2 expression has been observed in prostate cancers. In a phase 1/2 multicenter trial (NCT01631552), a patient in the mCRPC subgroup (n = 11) achieved a complete response following treatment with sacituzumab govitecan.⁶

In another phase 2 trial (NCT03725761), investigators examined the safety and efficacy of sacituzumab govitecan among patients with mCRPC who had progressed on second-generation androgen receptor–directed therapy. The coprimary end points of the trial were 6-month radiographic progression-free survival (rPFS) rate and PSA50.⁷

Among 20 patients who were treated with sacituzumab govitecan, the 6-month rPFS rate was 59%. The median rPFS was 8.1 months (95% CI, 2.0-13.1). Although no PSA50 responses were observed, patients who achieved a 6-month rPFS were found to stabilize PSA. Investigators concluded that these interim findings suggest the agent has activity in mCRPC, however the limited sample sizes necessitates further validation.⁷

The final ADC Dallos discussed in mCRPC was the CD46-directed agent FOR46. CD46 is specific for prostate tumors as well as being unregulated by androgen receptor–signaling inhibitors. FOR46 is an ADC with amonomethyl auristatin E payload that has displayed significant preclinical activity.⁸

In a phase 1 trial (NCT03575819), 51 patients with mCRPC, 92% of whom displayed CD46 expression, who previously received an androgen receptor-signaling inhibitors but had not yet received chemotherapy were treated with FOR46. The PSA50 response rate was 37% and the ORR was 48%. The median duration of PSA50 response was at least 16 weeks (range, 6-46+). Regarding safety, the most significant toxicity was neutropenia, according to Dallos.⁸

Third-Generation Androgen Signaling Inhibitors

Dallos transitioned his presentation to the discussion of androgen receptor signaling inhibitors. The first one that he touched on was bavdegalutamide (ARV-110), a first-in-class, oral proteolysis targeting chimera protein degrader that selectively targets the androgen receptor. The agent is being evaluated in a phase 1/2 trial (NCT0388861).⁹

Findings from phase 1 showed that the PSA50 response rate was 17% and the PSA30 response rate was 43% among 46 patients who received bavdegalutamide. Notably, patients with androgen receptor T878X/H875–-positive tumors (n = 26) achieved a PSA50 response rate of 40%.⁹

Bavdegalutamide was found to be very well tolerated, with no grade 4 TRAEs. The most common any-grade TRAEs reported at the recommended phase 2 dose were nausea (42%), fatigue (27%), vomiting (23%), decreased appetite (19%), diarrhea (15%), and alopecia (11%).⁹

Dallos concluded his presentation by talking through data from a novel N-terminal domain inhibitor: EPI-7386.

In part 1a of the first-in-human trial of EPI-7386 in mCRPC (NCT04421222), the agent was found to be very well tolerated with mild gastrointestinal toxicity and fatigue. Among 45 patients, any grade TRAEs consisted of nausea (20%), fatigue (20%), diarrhea (13.3%), hot flush (8.8%), and increased aspartate aminotransferase (4.4%). No dose-limiting toxicities were observed.¹⁰

Seventeen patients remained on study for more than a year, 9 of whom had measurable disease at baseline. Decreases in measurable disease were observed in 7 of these patients, even in the absence of PSA decrease. Dallos noted that 1 patient also experienced a PSA50 response.

Investigators concluded that the agent achieved target clinical exposures, and showed preliminary signs of antitumor activity in a patient subset primarily driven by androgen receptor alterations. The phase 1b dose expansion phase is ongoing, and the agent is also being tested in combination with enzalutamide, Dallos concluded.¹⁰

References

1. Dallos M. Novel targets for advanced castration-resistant prostate cancer: ADCs, novel AAs, and other new therapies. March 10-11, 2023. New York, NY.
2. Petrylak DP, Vogelzang NJ, Chatta K, et al. PSMA ADC monotherapy in patients with progressive metastatic castration-resistant prostate cancer following abiraterone and/or enzalutamide: efficacy and safety in open-label single-arm phase 2 study. Prostate. 2020;80(1):99-108. doi:10.1002/pros.23922
3. Guo C, Figueiredo I, Gurel B, et al. B7-H3 as a therapeutic target in advanced prostate cancer. Eur Urol. 2023;83(3):224-238. doi:10.1016/j.eururo.2022.09.004
4. Shenderov E, Mallesara GHG, Qysocki PJ, et al. MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors: preliminary results of phase I cohort expansion. Ann Oncol. 2021;32(suppl 5):S626-S677. doi:10.1016/j.annonc.2021.08.1133
5. Doi T, Patel M, Falchook GS, et al. DS-7300 (B7-H3 DXd antibody-drug conjugate [ADC]) shows durable antitumor activity in advanced solid tumors: extended follow-up of a phase I/II study. Ann Oncol. 2022;33(suppl 7):S197-S224. doi:10.1016/j.annonc.2022.07.582
6. Bardia A, Messersmith WA, Kio EA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021;32(6):746-756. doi:10.1016/j.annonc.2021.03.005
7. Lang J, Tagawa ST, Slovin S, et al. Interim results of a phase II trial of sacituzumab govitecan (SG) in patients (Pts) with metastatic castration resistant prostate cancer (mCRPC) progressing on androgen receptor signaling inhibitors (ARSI). Ann Oncol. 2022;33(suppl 7):1188. doi:10.1016/j.annonc.2022.07.1892
8. Aggarwal R. Targeting a tumor-specific CD46 epitope in metastatic castration resistant prostate cancer. Presented at: 29th Annual Prostate Cancer Foundation Scientific Retreat; October 27, 2022. Accessed March 10, 2023. https://www.pcf.org/scientific-retreat/29th-annual/
9. Gao X, Burris HA, Vuky J, et al. Phase 1/2 study of ARV-110, an androgen receptor (AR) PROTAC degrader, in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 6):17. doi:10.1200/JCO.2022.40.6_suppl.017
10. Pachynski R, Iannotti N, Laccetti, et al. A phase 1 trial of oral EPI-7386 in patients with metastatic castration-resistant prostate cancer (mCRPC): update from the first-in-human study. J Clin Oncol. 2023;41(suppl 6):177. doi:10.1200/JCO.2023.41.6_suppl.177