Missed ASCO 2022 this year? Data presented at the 2022 annual meeting of the American Society of Clinical Oncology (ASCO 2022) solidified the role of doublet therapy—androgen-deprivation therapy (ADT) combined with a novel oral antiandrogen drug—for treatment of men with metastatic hormone-sensitive prostate cancer (mHSPC). Additional data were also presented on lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), which can be used to facilitate treatment sequencing decisions and patient selection for men with metastatic castration resistant prostate cancer (mCRPC).
The first presentation detailed results from the CHART trial, a study of 654 men with high-volume de novo mHSPC. The definition of high-volume disease in this trial was consistent with that in prior studies, ie, visceral disease or disease in which the patient had ≥4 bone metastases. A total of 20% of the study population had visceral disease and 46% had >20 bone lesions. Patients were randomized 1:1 to receive standard ADT (ie, luteinizing hormone-releasing hormone agonists or antagonists, or surgical castration) plus either SHR3680 (a novel second-generation antiandrogen given orally once daily; treatment arm) or bicalutamide (control arm).
The primary endpoints of the study were radiographic progression-free survival (rPFS) and overall survival (OS). The study met its primary endpoint. At 2 years, 72% of men in the treatment arm were free from radiographic progression, compared with 50% of men in the control arm (hazard ratio [HR] for rPFS, 0.44; 95% confidence interval [CI], 0.33–0.58). Additionally, 81% of men in the treatment arm remained alive compared with 70% of men in the control arm (HR for OS, 0.58; 95% CI, 0.44– 0.77). SHR3680 was also associated with a longer time to the next skeletal-related event (median not reached in the treatment arm vs 38.7 months in the control arm), longer time to prostate-specific antigen (PSA) progression (median not reached in the treatment arm vs 11 months in the control arm), and had a higher PSA undetectable rate (68% in the treatment arm vs 33% in the control arm).
Side effects of treatment for patients in the SHR3680 treatment arm were similar to what was seen in the control arm, and similar to the side effect profiles for the antiandrogen drug class. The most common morbidities were weight gain, hypertriglyceridemia, hypercholesterolemia, and aspartate aminotransferase elevation. This highlights the point that cardiometabolic health is a key consideration in the ongoing care of patients with advanced prostate cancer. Data collected using quality of life (QOL) measures suggest that QOL was better for patients in the treatment arm than for those in the control arm. It is important to note that this study and the development of SHR3680 were conducted entirely outside of the United States, and the drug is not currently available in the United States. Its future availability remains to be seen.
Updated data from ENZAMET were also presented. ENZAMET was a study of 1,125 men with mHSPC who were randomized 1:1 to ADT combined with enzalutamide (treatment arm). or a nonsteroidal antiandrogen (bicalutamide, nilutamide, or flutamide) in the control arm. In the treatment arm, 67% of men were alive at 5 years compared with 57% in the control arm (HR, 0.70; 95% CI, 0.58–0.84). A benefit was seen in men with both low-volume and high-volume disease. Taken together with the results from CHART, these studies highlight that intensification of ADT produces long-term survival benefits for men with mHSPC. While the ENZAMET investigators also conducted exploratory analysis in men who were also prescribed docetaxel, there was no significant benefit seen with the combination of ADT and enzalutamide plus docetaxel.
However, the study was not designed to answer the question of whether or not enzalutamide should be added to ADT and docetaxel. Therefore, this study cannot be used to draw conclusions in support of or against the use of triplet therapy. Additional data presented on the use of 177Lu-PSMA-617 therapy came from reports on the THERA-P and VISION trials. THERA-P trial is a phase 2 randomized controlled trial in men previously treated with docetaxel. The study randomized 200 men 1:1 to 177Lu-PSMA-617 (up to 6 cycles) or intravenous cabazitaxel (20 mg/m2 every 3 weeks, up to 10 cycles).
The authors had previously presented data on the primary endpoint showing increased PSA response with 177Lu-PSMA-617 compared with cabazitaxel. After a median of 3 years, however, they found no difference in OS between the 2 groups. Notably, however, there were fewer adverse events and better patient-reported outcomes in the 177Lu-PSMA-617 treatment group compared with the cabazitaxel group. The researchers posited that, based on these data, it seems reasonable to use 177Lu-PSMA-617 in the post-docetaxel, post-androgen receptor–targeting agent setting, before cabazitaxel chemotherapy.
Data presented from the VISION trial focused on patient selection. They reported that patients who are likely to have the best response to 177Lu-PSMA-617 in that trial are those whose disease has a high mean standardized uptake value (SUV), ie >10, on PSMA– positron emission tomography/computed tomography. Those whose disease has a low mean SUV have a less robust response to 177Lu-PSMA-617 treatment.
In conclusion, doublet (and sometimes triplet) therapy can be considered an established tool in the treatment armamentarium for men with mHSPC detected by conventional scans. 177Lu-PSMA-617 is most beneficial for those whose disease has a high SUV on PSMA PET/ CT. Although it does not prolong OS compared with cabazitaxel, it results in better patient-reported outcomes and fewer side effects, making it a reasonable treatment option before second line chemotherapy.
Catherine H. Marshall, MD, MPH, is assistant professor of oncology at The Johns Hopkins School of Medicine, Baltimore, Maryland.