Article

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

Author(s):

Patients with metastatic castration-resistant prostate cancer 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 population.

Matthew Dallos , MD

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
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