SHR3680 Plus ADT Improves Survival Vs Bicalutamide/ADT in High-Volume mHSPC

The addition of SHR3680 to androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) compared with bicalutamide (Casodex) plus ADT in patients with high-volume, metastatic hormone-sensitive prostate cancer (mHSPC), according to data from the phase 3 CHART trial (NCT03520478).

Findings from a preliminary analysis, which had a data cutoff of May 16, 2021, showed that patients in the SHR3680/ADT arm (n = 324) achieved a median rPFS that was not yet reached (NR; 95% CI, NR-NR) at a median follow-up of 22.1 months per independent review committee (IRC), compared with 25.1 months (95% CI, 15.7-NR) for patients in the bicalutamide/ADT arm (n = 323) at a median follow-up of 20.4 months (HR, 0.44; 95% CI, 0.33-0.58; P < .0001). The 24-month rPFS rates were 72.3% and 50% in the investigative and control arms, respectively.

Updated data, which had a cutoff of February 28, 2022, showed that SHR3680 prolonged rPFS vs bicalutamide in this patient population. The median rPFS with SHR3680/ADT was still NR (95% CI, NR-NR) vs 23.5 months (95% CI, 15.7-30.2) in the bicalutamide/ADT arm, translating to a 54% lower risk of radiographic disease progression or death (HR, 0.46; 95% CI, 0.36-0.60). The 24-month rPFS rates with SHR3680 and bicalutamide were 72.9% and 49.4%, respectively.

Moreover, SHR3680 was reported to significantly prolong OS vs bicalutamide, even though the median OS was NR in both the investigative (95% CI, NR-NR) and control (95% CI, 36.2-NR) arms. The addition of SHR3680 to ADT lowered the risk of death in patients by 42% (HR, 0.58; 95% CI, 0.44-0.77; P = .0001). The 24-month OS rates were 81.6% in the SHR3680 arm and 70.3% in the bicalutamide arm.

Although phase 3 TITAN (NCT02489318) and ARCHES (NCT02677896) trials both demonstrated the benefits achieved with second-generation androgen receptor inhibitors (ARIs) in combination with ADT in the treatment of patients with mHSPC, first-generation ARIs plus ADT is another approach that is also widely used in clinical practice, and the advantage of second-generation agents over first-generation remains unclear.

SHR3680 is a novel, oral ARI, and the CHART trial aimed to evaluate the safety and efficacy of the agent in combination with ADT vs the first-generation ARI bicalutamide plus ADT.

CHART enrolled patients who were at least 18 years of age who had a pathological diagnosis of prostate adenocarcinoma. Patients were required to have an ECOG performance status of 0 or 1 and high-volume disease, defined as at least 4 bone lesions with at least 1 beyond the vertebral column or pelvis, or visceral metastasis.

Patients were not allowed to have received prior treatment with ADT, chemotherapy, surgery, or localized treatment, except for up to 3 months of ADT with or without a first-generation ARI, or a single course of palliative radiotherapy or surgery for metastatic symptoms at least 4 weeks prior to start of study treatment.

Study participants were randomized 1:1 to receive 240 mg of oral SHR3680 daily plus ADT, or 50 mg of oral bicalutamide daily plus ADT. Treatment cycles lasted for 28 days, and treatment was continued until disease progression, intolerable toxicity, withdrawn consent, or investigator decision.

The co-primary end points of the trial included IRC-assessed rPFS of soft-tissue lesions per RECIST v1.1 criteria and bone lesions per PCWG3 criteria, as well as OS. Investigator-assessed rPFS, time to prostate-specific antigen (PSA) progression, time to next skeletal-related event, time to initiation of a new anti–prostate cancer therapy, overall response rate (ORR), and safety comprised the secondary end points. Exploratory end points included PSA response rate, PSA undetectable rate, and patient-reported outcomes.

The median age of all patients was 69 years (range, 64-75), and most of those in the SHR3680 and bicalutamide arms were younger than 70 years (51.8% vs 51.2%, respectively), from China (90.5% vs 90.2%), had an ECOG performance status of 1 (74.2% vs 73.5%), did not have visceral metastases excluding lymph nodes (80.4% vs 78.7%), had more than 20 bone lesions (46.6% vs 46.6%), and had a Gleason score of at least 8 (84.7% vs 78.4%).

Moreover, most patients in the investigative and control arms, respectively, did not have baseline lactate dehydrogenase levels above the upper limit of normal (ULN; 74.8% vs 79.6%), had baseline alkaline phosphatase levels above ULN (66.9% vs 65.9%), had a baseline pain score of 0 (no pain; 62.3% vs 62.8%), received prior ADT (56.1% vs 56.7%), and received prior antiandrogen therapy (82.5% vs 82.3%). The median PSA levels at baseline were 78.8 ng/mL (interquartile range [IQR], 12.8-314.4) in the SHR3680 arm and 51.3 ng/mL (IQR, 8.1-231.7) in the bicalutamide arm.

Of the 326 patients enrolled to the SHR3680 arm, 324 received the study drug; 328 patients were enrolled to the bicalutamide arm, and 323 received treatment. At the time of data cutoff, 191 patients and 60 patients were ongoing treatment in the SHR3680 and bicalutamide arms, respectively.

Reasons for stopping treatment in the investigative and control arms, respectively, included radiographic progression (21.2% vs 35.7%), clinical progression (7.1% vs 15.2%), patient withdrawal (5.8% vs 17.7%), investigator decision (3.4% vs 7.9%), death (1.8% vs 2.1%), adverse effects (AEs; 0.6% vs 0.9%), protocol violation (0% vs 0.3%), new anticancer treatment (0.3% vs 0%), loss to follow-up (0.3% vs 0%), and another unspecified reason (0.3% and 0.3%).

The median treatment exposure was 28.9 months (IQR, 16.9-35.4) in the SHR3680 group vs 12.9 months (IQR, 7.3-25.5) in the bicalutamide group.

Additional data showed that the median rPFS per investigator assessment was NR (95% CI, NR-NR) in the SHR3680/ADT arm vs 18.5 months (95% CI, 14.8-25.7) in the bicalutamide/ADT arm (HR, 0.39; 95% CI, 0.30-0.50).

The median time to PSA progression in the SHR3680/ADT arm was also NR (95% CI, NR-NR) compared with 11.0 months (95% CI, 9.2-12.9) in the bicalutamide/ADT arm (HR, 0.21; 95% CI, 0.16-0.27). Moreover, the median time to next skeletal event was NR (95% CI, NR-NR) in the SHR3680/ADT arm vs 38.7 months (95% CI, 30.7-NR) in the bicalutamide/ADT arm. Lastly, for those who received SHR3680/ADT, the median time to new anti–prostate cancer treatment was NR (95% CI, NR-NR) vs 15.2 months (95% CI, 13.7-18.1) in those who received bicalutamide/ADT (HR, 0.33; 95% CI, 0.26-0.41).

The combination of SHR3680 and ADT elicited an IRC-assessed ORR of 81.0% vs 67.9% with bicalutamide plus ADT. In the investigative and control arms, the PSA response rates were 94.4% and 78.9%, respectively; the PSA undetectable rates were 68.7% and 33.5%, respectively.

Additional assessments showed that patients in the SHR3680 group experienced better quality of life over time than those in the bicalutamide group.

Regarding safety, AEs were reported in 98.1% of patients in both arms, and grade 3 or higher AEs were experienced by 51.4% and 42.3% of those in the SHR3680 and bicalutamide arms, respectively. In the SHR3680 arm, AEs led to treatment discontinuation, interruption, reduction, or death in 1.5%, 12.4%, 2.8%, and 4.0% of patients, respectively; in the bicalutamide arm, those rates were 1.5%, 5.9%, 0%, and 4.3%, respectively.

The most common AEs of any grade reported in the SHR3680 and bicalutamide arms, respectively, included increased weight (46.7% vs 43.2%), hypertriglyceridemia (27.9% vs 15.4%), increased aspartate aminotransferase (20.1% vs 12.7%), hypercholesterolemia (19.5% vs 15.7%), increased alanine aminotransferase (19.2% vs 12%), anemia (18.6% vs 17%), hypertension (16.4% vs 11.1%), hot flush (14.6% vs 9.3%), hyperglycemia (12.4% vs 11.7%), and fatigue (10.2% vs 8.6%).

Reference

Ye DW, Gu W, Han W, et al. A phase 3 trial of SHR3680 versus bicalutamide in combination with androgen deprivation therapy (ADT) in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2022;40(suppl 16):5005. doi:10.1200/JCO.2022.40.16_suppl.5005