Expert Charts the Changing Treatment Landscape in CRPC

Matthew Dallos, MD, established therapies that are beginning to move into earlier lines of treatment, emerging antibody-drug conjugates (ADCs), and the potential of third generation anti-androgen agents in advanced castration-resistant prostate cancer (CRPC) in a presentation during the 16th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, hosted by Physicians’ Education Resource®, LLC (PER®).

Dallos, an assistant attending physician in the solid tumor genitourinary service at Memorial Sloan Kettering Cancer Center in New York City, spoke about the limitations of androgen receptor signaling inhibitor (ARSI) therapy in this disease space, how they might be filled by other agents, and novel targets which may further expand the quantity of treatment options for patients with advanced prostate cancers.

Changing Androgen Receptor Signaling Inhibitors Will Not be Standard of Care

With so many emerging options within the CRPC space, sequencing therapies becomes a notable question, with deciding factors including co-morbidities, disease volume, previous treatments, and disease histology. However, Dallos indicated that changing ARSIs will not become standard-of-care for this patient population.

In particular, he focused in findings from the phase 4 CARD study (NCT02485691) comparing the taxane cabazitaxel (Jevtana) with the ARSIs abiraterone (Zytiga) or enzalutamide (Xtandi) in patients with CRPC who were previously treated with docetaxel and experienced progression within 12 months of receiving an ARSI.¹ The investigators identified a progression-free survival (PFS) benefit in the cabazitaxel arm compared with the ARSI arm (HR 0.52; 95% CI, 0.40-0.68; P < .001) as well as an overall survival (OS) benefit (HR 0.64; 95% CI, 0.46-0.89; P = .008).

Dallos remarked that “switching” to ARSI therapy following a prior ARSI will, therefore, not become a standard of care in 2023.

PARP Inhibition Shows Promise in BRCA-Mutant Patients

PARP inhibitors have demonstrated synergy with AR antagonists in preclinical models. Based on this, Dallos discussed whether PARP inhibitors are best used in certain biomarker-selected populations or in all-comers.

He highlighted data from the phase 3 PROfound study (NCT02987543), which compared the PARP inhibitor olaparib (Lynparza) with a control regimen of enzalutamide or abiraterone plus prednisone in a population of patients with metastatic CRPC.²

In Cohort A of the trial—which contained patients with BRCA alterations—the median imaging-based PFS was 7.4 months in the olaparib group vs 3.6 months in the control group (HR 0.34; 95% CI, 0.25-0.47; P <.001). Investigators also reported a significant improvement in confirmed objective response rate (ORR) and the time to pain progression with olaparib.

Later data also showed a median OS of 14.1 months with olaparib vs 11.5 months with the control therapy in cohort B, which was comprised of patients without BRCA mutations.³ In the overall population, median OS was 17.3 months and 14.0 months, respectively. Median OS in cohort A was 19.1 months and 14.7 months with olaparib and control therapy, respectively (HR 0.69; 95% CI, 0.50-0.97; P = .02)

Although the benefit from olaparib occurred across both cohorts and led to the FDA approval of olaparib in patients with all homologous recombination mutations.⁴ Dallos explained that patients with BRCA alterations derived the greatest advantage from the treatment.

He next shifted to the phase 3 TRITON3 trial (NCT02975934), assessing rucaparib (Rubraca) compared with physician’s choice control therapy in patients with a BRCA mutation.⁵ Findings from this study showed a median imaging-based PFS of 11.2 months with rucaparib vs 6.4 months with control therapy in the BRCA subgroup (HR 0.50; 95% CI, 0.36-0.69, P <.001).

A PFS advantage was also reported in the intention-to-treat subgroup (HR 0.61; 95% CI, 0.47-0.80; P <.001).

The physician’s choice therapy in this trial consisted either of docetaxel or an ARSI. Dallos noted that, like olaparib, rucaparib seemed to outperform these agents in patients with advanced/metastatic CRPC who progressed following a prior ARSI.

Combining Tyrosine Kinase and Immune Checkpoint Inhibitors

When detailing combination regimens for patients with metastatic disease, Dallos highlighted findings from cohort 6 of the phase 1b/2 COSMIC-021 study (NCT03170960), which assessed the tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx) in combination with the immune checkpoint inhibitor (ICI) atezolizumab (Tecentriq) in metastatic CRPC.⁶

Investigators reported an ORR per RECIST 1.1 criteria of 32% across 44 patients, including 2 complete responses (CRs; 4.5%) and 12 partial responses (PRs; 27%). Moreover, a further 21 (48%) patients had stable disease, and the disease control rate (DCR) was 80%.

Dallos also highlighted the ongoing phase 3 CONTACT-02 trial (NCT04446117), which is assessing cabozantinib plus atezolizumab vs a second novel hormone therapy (NHT) in patients with advanced or nonmetastatic prostate cancer who have previously received an NHT.

Pursuing Future Targets in CRPC

Future efforts in the CRPC space will likely be focused on targeting tumor cells and the tumor microenvironment, as well as mitigating mechanisms of resistance, according to Dallos. Several targets are currently under investigation that may be targeted by ADCs and third generation ARSIs.

B7-H3 has been associated with recurrence and poor outcomes in patients, although its function isn’t currently understood. As such, the potential target is under investigation in a phase 1 study (NCT03729596) along with investigational ADC MGC018. The agent has a duocarmycin payload linked to an anti­–B7-H3 monoclonal antibody.⁷

Early data have shown promise and future updates are expected. Another anti­–B7-H3 ADC DS-7300 demonstrated durable anti-tumor activity, according to early findings from a phase ½ first-in-human study (NCT04145622).⁸

Trop-2 is also has been assessed as a target in patients with metastatic urothelial carcinoma and breast cancer who were treated with sacituzumab govitecan-hziy (Trodelvy). As, prostate tumors are known to have a high Trop-2 expression, a phase 2 trial (NCT03725761) will assess sacituzumab govitecan as a treatment for metastatic CRPC following ARSI.

CD46 is another target specific to prostate tumors and has thus far been unregulated by ARSI. As such, a phase 1 study (NCT03575819) will assess FOR46, a CD46-directed ADC, following ARSI and before chemotherapy; thus far early data appear favorable and the most notable toxicity was neutropenia, according to Dallos.⁹

AR degraders are also a point of interest. Bavdegalutamide (ARV-110), a novel androgen receptor (AR) degrader, appeared clinically active and tolerable in patients with CRPC following 1 to 2 prior NHT agents, according to data from the phase 1/2 ARDENT trial (NCT03888612).¹⁰ Investigators noted that the most significant responses were in those with T878X/H875Y mutations.

Lastly, Dallos highlighted the potential benefit of inhibiting steroid synthesis. ODM-208, which targets CYP11A1, appeared to yield clinically favorable outcomes following ARSI and a taxane, according to early data from the phase 1/2 CYPIDES trial (NCT03436485).¹¹

Dallos concluded by speaking to the importance of matching patients with the right treatment, which includes tackling the challenges of inter- and intra-patient heterogeneity and tumor evolution. Several strategies including advanced imaging, next-generation sequencing, cfDNA, circulating tumor cells, and artificial intelligence may play a role in patient selection.

References

1. de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206
2. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
3. Hussain M, Mateo J, Fizazi K, et al; PROfound Trial Investigators. Survival with olaparib in metastatic castration-resistant prostate cancer. N Engl J Med. 2020;383(24):2345-2357. doi:10.1056/NEJMoa2022485
4. FDA approves olaparib for HRR gene-mutated metastatic castration-resistant prostate cancer. News release. AstraZeneca. May 19, 2020. Accessed March 14, 2023. http://bit.ly/3JgB4Qv
5. Fizazi K, Piulats JM, Reaume MN, et al; TRITON3 Investigators. Rucaparib or physician's choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732. doi:10.1056/NEJMoa2214676
6. Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results of cohort 6 of the COSMIC-021 study. J Clin Oncol. 2020;38(suppl 15):5564. doi:10.1200/JCO.2020.38.15_suppl.5564
7. Shenderov E, Mallesara GHG, Wysocki 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):S657-S659. doi:10.1016/j.annonc.2021.08.1133
8. 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/annonc/annonc1049
9. Aggarwal RR, Vuky J, VanderWeele DJ, et al. Phase 1a/1b study of FOR46, an antibody drug conjugate (ADC), targeting CD46 in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 16):3001. doi:10.1200/JCO.2022.40.16_suppl.3001
10. 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. J Clin Oncol. 2022;40(suppl 6):17. doi:10.1200/JCO.2022.40.6_suppl.017
11. Fizazi K, Bernard-Tessier A, Barthelemy P, et al. Preliminary phase II results of the CYPIDES study of ODM-208 in metastatic castration-resistant prostate (mCRPC) cancer patients. Ann Oncol. 2022;33(suppl 7):S616-S652. doi:10.1016/annonc/annonc1070