2021 Genitourinary Cancers Symposium
Novel and Emerging Treatments for Progressive Metastatic Castration-Resistant Prostate Cancer
As seen at the 2021 Genitourinary Cancers Symposium, targeted radionuclide therapy and other precision and immune-based treatments promise to deliver incremental gains for men with progressive metastatic castration-resistant prostate cancer (mCRPC).
Our featured expert, William K. Oh, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD, and Dr Oh’s perspectives on these emerging data are presented here.
Clinical Professor of Medicine
“Emerging data with targeted radionuclides, genomically targeted therapy, and immunotherapy are all encouraging as we continue to try to improve outcomes in mCRPC.”
Recent developments in the testing for potentially actionable biomarkers, such as prostate-specific membrane antigen (PSMA), in progressive mCRPC are allowing us to individualize therapies based on tumor characteristics. Emerging data with targeted radionuclides, genomically targeted therapy, and immunotherapy are all encouraging as we continue to try to improve outcomes in mCRPC.
The first abstract in this section, abstract 6, described updated results from the randomized phase 2 TheraP trial, including data on progression-free survival (PFS), radiographic PFS (rPFS), prostate-specific antigen (PSA)–PFS, and objective response rate (ORR). Initial results from the TheraP study showed exciting response rates with 177Lu-PSMA-617 (Lu-PSMA) compared with cabazitaxel in men with mCRPC. Among those who progressed with docetaxel, with 91% of patients also treated with prior enzalutamide/abiraterone, Lu-PSMA significantly improved PSA responses (defined by a ≥50% reduction) compared with cabazitaxel (66% vs 37%). In this abstract, Hofman and colleagues also reported improved PFS at 1 year with Lu-PSMA compared with cabazitaxel (19% vs 3%); similar benefits were seen with rPFS and PSA-PFS. Additionally, ORR in patients with measurable disease was significantly greater in men treated with Lu-PSMA than in those treated with cabazitaxel (49% vs 24%). While Lu-PSMA demonstrated improved outcomes, we have more work to do, as only 19% of patients were progression free at 1 year. Still, these agents work, and, if they are used earlier in the disease course, there might be a more durable long-term effect.
Patients in this trial had high PSMA expression and no sites of FDG-positive/PSMA-negative disease, so it is a selected population of men with mCRPC. A good number of Lu-PSMA–treated patients experienced dry mouth and some reported dry eyes, compared with cabazitaxel-treated patients. In addition, grades 3/4 thrombocytopenia were reported in 11% of men who received Lu-PSMA and in no patients who received cabazitaxel. Overall, however, I think that the findings from this analysis are promising, especially in the third-line setting, and may provide an alternative to additional chemotherapy in this patient population.
Another study generating significant interest at the 2021 Genitourinary Cancers Symposium was IPATential150 (abstract 13). Ipatasertib is an orally available small molecule that targets tumors with PTEN loss and blocks activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. It is of great interest because it might be the next targeted therapy to emerge beyond poly (ADP-ribose) polymerase inhibitors, also commonly known as PARP inhibitors. Previously reported data from the IPATential150 trial demonstrated that first-line treatment with ipatasertib plus abiraterone significantly reduced the risk of disease worsening or death compared with placebo plus abiraterone in men with mCRPC who had tumors with PTEN loss. PTEN loss was identified by immunohistochemistry, which is an indirect measure of the pathway that ipatasertib targets. In abstract 13, de Bono et al reported their findings with the use of a more stringent identification of PTEN loss, including the use of next-generation sequencing to detect genomic alterations along the PI3K/AKT pathway. They found that the benefits of ipatasertib plus abiraterone were magnified in the more stringently defined subsets. Thus, I believe that this type of approach may allow us to more precisely identify the patients who would stand to benefit from targeting this cancer pathway.
Finally, another developing area is immuno-oncology. Most men with prostate cancer are not offered checkpoint inhibitors, as prostate cancer appears to be minimally responsive to single-agent checkpoint inhibition. However, questions regarding the potential for rational combinations are intriguing (eg, whether cytotoxic chemotherapy interferes with the immune response needed for immune checkpoint inhibition).
KEYNOTE-365 was part of a larger cohort of studies in which pembrolizumab was combined with various drugs that have known activity in prostate cancer. Abstract 10 provided an update on cohort B, which is the combination of pembrolizumab plus docetaxel and prednisone in patients with mCRPC who already received abiraterone or enzalutamide. The authors concluded that, after another year of follow-up, pembrolizumab plus docetaxel and prednisone resulted in improved ORRs and PSA response rates compared with the prior dataset. Additionally, the side-effect profile was similar to what is expected with each of the drugs separately; however, 4.8% of patients died from adverse events, which could be due to chemotherapy or immunotherapy.
Although these responses are encouraging, there are limited data available to determine a synergistic effect when combining pembrolizumab and docetaxel. I think that we should remain cautious when using 2 drugs that alter the immune system differently. Nevertheless, this abstract showed that pembrolizumab and docetaxel can maintain efficacy and be combined relatively safely, and I am eagerly awaiting the results of the phase 3 KEYNOTE-921 study. I do think that we will see some very exciting advancements in the immuno-oncology space for prostate cancer in the future, including bispecific antibodies and chimeric antigen receptor T cells. Further, PSMA as an immune target for patients with prostate cancer has tremendous potential.
Appleman LJ, Kolinsky MP, Berry WR, et al. KEYNOTE-365 cohort B: pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)–pretreated patients with metastatic castration-resistant prostate cancer (mCRPC)—new data after an additional 1 year of follow-up [abstract 10]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
ClinicalTrials.gov. Study of pembrolizumab (MK-3475) plus docetaxel versus placebo plus docetaxel in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) (MK-3475-921/KEYNOTE-921). Accessed March 3, 2021. https://clinicaltrials.gov/ct2/show/NCT03834506
de Bono JS, Bracarda S, Sternberg CN, et al. IPATential150: phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC) [abstract LBA4]. Abstract presented at: ESMO Virtual Congress 2020; September 19-21, 2020.
de Bono JS, De Giorgi U, Rodrigues DN, et al. Randomized phase II study evaluating Akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res. 2019;25(3):928-936. doi:10.1158/1078-0432.CCR-18-0981
de Bono JS, Sweeney C, Bracarda S, et al. PI3K/AKT pathway biomarkers analysis from the phase III IPATential150 trial of ipatasertib plus abiraterone in metastatic castration-resistant prostate cancer [abstract 13]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
Herberts C, Murtha AJ, Fu S, et al. Activating AKT1 and PIK3CA mutations in metastatic castration-resistant prostate cancer. Eur Urol. 2020;78(6):834-844. doi:10.1016/j.eururo.2020.04.058
Hofman MS, Emmett L, Sandhu SK, et al. 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel: updated results including progression-free survival (PFS) and patient-reported outcomes (PROs) (TheraP ANZUP 1603) [abstract 6]. Abstract presented at: 2021 Genitourinary Cancers Symposium; February 11-13, 2021.
Hofman MS, Emmett L, Sandhu S, et al; TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804. doi:10.1016/S0140-6736(21)00237-3
Kolinsky MP, Gravis G, Mourey L, et al. KEYNOTE-365 cohort B updated results: pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(suppl 6):103. doi:10.1200/JCO.2020.38.6_suppl.103
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