Pfizer Showcases Leadership in Urologic Oncology at ASCO 2024 with Multiple Innovative Therapies and Clinical Data

Jun 13, 2024 19:59 CST Updated 20:01

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Focusing on Urological Tumors, Gaining Insights into Cutting-edge Advances.

Listen to the Academic Echo of the ASCO Conference, Dive into the Ocean of Knowledge on Urological Tumors. From May 31 to June 4, 2024, Eastern Time, the annual American Society of Clinical Oncology (ASCO) conference was grandly held in Chicago. The conference announced the latest advancements in various types of tumors. In the field of urological tumors, including updates in kidney cancer, prostate cancer, and urothelial cancer research, it has drawn enthusiastic attention from scholars in the urological field both in China and internationally. Genitourinary system tumors have always been one of the key areas Pfizer has focused on in cancer treatment. Over the years, Pfizer has brought many innovative therapies and excellent survival benefits to a large number of urological tumor patients, benefiting patients in China and globally. For instance, Axitinib in the field of kidney cancer; Talazoparib and Degarelix in prostate cancer; and Enfortumab Vedotin, a Nectin-4 targeted ADC drug used for urothelial cancer.

Renal Cancer

Among the relevant research advances presented at this year's ASCO conference, studies on clear cell renal cell carcinoma (ccRCC) dominate in the field of kidney cancer. In terms of disease stages, abstracts related to first-line treatment for metastatic renal cell carcinoma (mRCC) were the most numerous. Regarding treatment modalities, immunotherapy remains the main focus of research exploration in the kidney cancer field. Concerning first-line treatment regimens for kidney cancer, based on the results of the KEYNOTE-426 and JAVELIN Renal 101 studies, in 2019, the U.S. FDA approved two regimens—pembrolizumab + axitinib and avelumab + axitinib—for first-line treatment of advanced kidney cancer, marking the beginning of the combination era of targeted therapy and immunotherapy for advanced kidney cancer. Based on the results of the RENOTORCH study, in April 2024, China’s National Medical Products Administration (NMPA) approved the indication of toripalimab combined with axitinib for first-line treatment of advanced RCC, signifying that first-line treatment for advanced kidney cancer in China has officially entered the era of combined targeted and immune therapy.

Axitinib

KEYNOTE-426 is the first randomized controlled clinical study in the field of advanced renal cell carcinoma to compare targeted-immunotherapy combination treatment with single-agent targeted therapy. Previously, the KEYNOTE-426 study released its 5-year long-term follow-up data.^[1]The results showed that the 60-month overall survival (OS) rates for the pembrolizumab + axitinib group and the sunitinib group were 41.9% and 37.1%, respectively, and the 60-month progression-free survival (PFS) rates were 18.3% and 7.3%, respectively. Pembrolizumab + axitinib, as a first-line standard treatment for advanced RCC, brings clear survival benefits to patients. The biomarker exploration results of this study were announced at the ASCO conference.^[2]The study results indicate that the T-cell inflammatory gene expression profile (Tcell inf GEP) is strongly correlated with clinical outcomes in the pembrolizumab plus axitinib group, whereas the PD-L1 CPS score shows no correlation with its clinical outcomes. Angiogenesis is positively associated with clinical outcomes in the sunitinib group. In the future, further understanding of the role of the immune microenvironment in combination therapy will be critical for selecting treatment strategies.

RENOTORCH Study^[3]It is the world's first randomized, controlled, multicenter Phase III clinical study using a targeted therapy combined with PD-1 monoclonal antibody for intermediate- to high-risk renal cell carcinoma (RCC), aiming to evaluate the efficacy and safety of Toripalimab combined with Axitinib versus Sunitinib in treating advanced RCC patients. The study results showed that the median PFS in the Toripalimab plus Axitinib group reached 18.0 months, compared to 9.8 months in the Sunitinib monotherapy group, with an HR of 0.65, reducing the risk of disease progression or death by 35%. The efficacy data of the combination of targeted therapy and immunotherapy nearly doubled compared to receiving targeted therapy alone. "2024 Edition CSCO Guidelines for Renal Cancer Diagnosis and Treatment"^[4]This year, the recommendation level for toripalimab combined with axitinib in the first-line treatment of metastatic or unresectable clear cell renal cell carcinoma has been upgraded to a Grade Ⅰ recommendation (1A class evidence). With the approval of relevant indications, it is expected that toripalimab combined with axitinib will bring tangible survival benefits to patients with advanced RCC in clinical practice.

Prostate Cancer

Prostate cancer had the most abstracts published among urological tumors at this year's ASCO conference, with research hotspots still focused on the treatment phase of metastatic castration-resistant prostate cancer (mCRPC). mCRPC is highly aggressive, with a generally poor prognosis and a median survival time of only 17.5-34.7 months. PARP inhibitors are a new type of targeted anti-cancer drug. In recent years, several Phase III clinical studies on PARP inhibitors have successively shown positive results in the treatment of mCRPC, offering survival benefits and new treatment options for patients with mCRPC.

Talazoparib

Talazoparib is a PARP inhibitor with a dual mechanism, which on one hand exerts cytotoxic effects through the "synthetic lethality" effect of PARP inhibitors. On the other hand, talazoparib is also capable of trapping PARP enzymes. TALAPRO-2 Study^[5]The primary endpoint was met, showing that talazoparib + enzalutamide significantly prolonged radiographic progression-free survival (rPFS) in the entire population (regardless of the presence of HRR gene mutations). In the overall patient population, talazoparib combined with enzalutamide significantly reduced the risk of radiographic progression by 37% (rPFS: NR vs. 21.9 months; HR=0.63); in the HRR-mutated population, the rPFS event risk for talazoparib combined with enzalutamide was significantly reduced by 55% (NR vs. 13.8 months, HR 0.45). Talazoparib is currently the *only PARP inhibitor that has demonstrated significant efficacy benefits in both HRR-mutated and the entire population.

Multiple biomarker findings from the TALAPRO-2 study were presented at this year’s ASCO conference. Results of ctDNA burden as a prognostic biomarker for efficacy.^[6]Indicates that patients with low ctDNA burden at baseline, patients with ctDNA transitioning from high to low levels, and patients maintaining low ctDNA levels from baseline to week 9 showed better rPFS benefits. This suggests that ctDNA burden is of great significance in evaluating the efficacy and prognosis of mCRPC.

Another exploratory analysis evaluating changes in circulating tumor cells (CTCs) and CTC0 as prognostic biomarkers of efficacy in the TALAPRO-2 study^[7]The results showed that in the TALAPRO-2 study, the reduction in CTC counts at weeks 9 and 17 in the two treatment groups demonstrated an improvement in rPFS. This is also the first time such a correlation has been confirmed in a Phase III study, supporting the value of CTC counts in predicting the efficacy and prognosis of mCRPC.

Degarelix

In addition to PARP inhibitors bringing new treatment options for mCRPC, androgen deprivation therapy (ADT) remains the cornerstone of treatment for advanced prostate cancer and is also crucial for high-risk prostate cancer, being widely used as adjuvant therapy post-surgery in high-risk patients. ADT is mainly achieved through bilateral orchiectomy, gonadotropin-releasing hormone (GnRH) agonists, or GnRH antagonists. The GnRH antagonist degarelix has the characteristics of rapidly lowering testosterone and PSA levels, prolonging PSA progression-free survival, and presenting a low risk of cardiovascular events and musculoskeletal adverse events.

In Phase III CS21 Study^[8]In China, the therapeutic effects of degarelix and the GnRH agonist leuprorelin were compared. The results showed that degarelix enabled patients to reach castration levels of testosterone more quickly. On the third day of degarelix treatment, 96% of patients reached castration levels of testosterone, whereas no patients reached this level on the third day of leuprorelin treatment. PANDA Study^[9]A Study to Explore the Efficacy/Safety of Degarelix versus the GnRH Agonist Goserelin in Chinese Patients with Prostate Cancer: Results Showed that Degarelix Rapidly Reduced Testosterone and PSA Levels, with a 96% Castration Rate by Day Three, While No Patients Treated with Goserelin Achieved This.

Given the widespread use of GnRH agonists in clinical practice, the CS21A study^[10]Evaluation of the Safety and Efficacy of Switching from Leuprolide to Degarelix. The results showed that for patients initially treated with leuprolide, switching to degarelix significantly prolonged PSA-PFS (P=0.002). For high-risk patients with PSA ≥20 ng/mL, switching to degarelix also significantly extended PSA-PFS (P=0.019), with improvements lasting over 5 years. Based on changes in follicle-stimulating hormone (FSH) levels after one year, degarelix demonstrated a deeper inhibitory effect on FSH compared to the control group using GnRH agonists, with percentage reductions in FSH from baseline being 89% and 54.8%, respectively.

Degarelix is the first and currently the *only GnRH antagonist launched in China, bringing new breakthroughs and treatment options to the field of prostate cancer treatment in the country. For metastatic prostate cancer, ADT remains the cornerstone of treatment. Degarelix can rapidly and profoundly reduce patients' testosterone levels without causing "testosterone flare." During long-term treatment, it keeps patients' testosterone levels consistently at castration levels, providing rapid and sustained benefits for prostate cancer patients. Degarelix is an optimized choice in ADT dual or triple therapy. With the implementation of the 2023 updated National Reimbursement Drug List (NRDL), Degarelix has also become a highly cost-effective option within ADT.

Urothelial Carcinoma

In the field of urothelial carcinoma (UC), platinum-based chemotherapy is the first-line standard treatment for locally advanced or metastatic UC. However, the efficacy of chemotherapy is limited, and many patients cannot tolerate platinum-containing chemotherapy. Exploring new treatment methods to improve efficacy and enhance patients' quality of life is one of the key goals in the UC field. In recent years, immunotherapy and novel antibody-drug conjugates (ADCs) have achieved breakthrough progress in the treatment of advanced UC.

Enfortumab vedotin

Enfortumab vedotin (EV) is an antibody-drug conjugate targeting nectin-4, EV-302^[11]It is an open-label, randomized, controlled Phase III trial aimed at evaluating the efficacy of EV combined with pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic UC. The study met its dual primary endpoints of OS and PFS, with nearly doubled OS and PFS benefits. Compared to platinum plus gemcitabine chemotherapy, patients receiving EV + pembrolizumab combination therapy had a median OS of 31.5 months, while the chemotherapy group had 16.1 months (HR=0.47); the median PFS was 12.5 months in the combination therapy group versus 6.3 months in the chemotherapy group (HR=0.45). Based on these results, the U.S. FDA approved EV in combination with pembrolizumab for first-line treatment of locally advanced or metastatic UC in December 2023.

The patient-reported outcomes (PRO) of EV-302 were orally presented at this year's ASCO.^[12]The study enrolled 731/886 patients (376 in the combination therapy group; 355 in the chemotherapy group) who completed baseline PRO reports. Differences in compliance were observed between groups, with over 70% of patients in the combination therapy group showing good compliance within 29 weeks, compared to only 17 weeks in the chemotherapy group. The median time to pain progression (TTPP) was 14.2 months for the combination therapy group and 10.0 months for the chemotherapy group. Among patients with moderate to severe baseline pain receiving combination therapy (128 patients, 34%), there was a significant improvement (>2 points) in the Brief Pain Inventory (BPI) worst pain score from week 3 to week 26 compared to baseline. Regarding the EORTC QLQ-C30 global health status/quality of life (GHS/QoL), the combination therapy group experienced a temporary deterioration (-6.3) at week 3 but returned to baseline levels from week 4 to week 26, whereas chemotherapy patients showed continuous deterioration (-1.2 to -7.1) from week 1 to week 17 before returning to baseline. The time to confirmed deterioration (TTCD) was 5.9 months for the combination therapy group and 3.2 months for the chemotherapy group. EV combined with pembrolizumab significantly improved patient survival without compromising quality of life, indicating the clinical value of this combination therapy for locally advanced and metastatic UC.

Summary

The treatment for advanced renal cell carcinoma mainly focuses on immunotherapy combined with anti-angiogenic drugs. The regimen of PD-1/PD-L1 inhibitors combined with Axitinib has been recommended by guidelines both in and outside China and has been approved for clinical use. Androgen deprivation therapy (ADT) remains the cornerstone treatment for prostate cancer. Degarelix is the first and currently the only Gonadotropin-releasing hormone (GnRH) antagonist available in China, offering more therapeutic advantages compared to GnRH agonists. PARP inhibitors have brought new treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). Talazoparib combined with Enzalutamide has been approved by the FDA for first-line treatment of mCRPC, and it is anticipated to be launched in China soon, providing more treatment choices for Chinese prostate cancer patients. The emergence of antibody-drug conjugates (ADCs) has revolutionized the treatment landscape for advanced urothelial carcinoma (UC). The combination of Enfortumab Vedotin (EV) and Pembrolizumab has challenged the status of platinum-based chemotherapy in advanced UC, potentially reshaping the first-line treatment paradigm and clinical practice for UC. Over the years, Pfizer has been deeply committed to the field of genitourinary cancers, with several approved drugs bringing significant survival benefits to patients worldwide. We look forward to further evidence from clinical studies, a more robust product pipeline, and the development and launch of more novel anti-cancer therapies to benefit patients globally.

*As of the date of this article

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References:

[1]Brian I. Rini, et al, Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426.2023 ASCO,LBA4501.

[2]Brian I., et al. Biomarker analysis of the phase 3 KEYNOTE-426 study of pembrolizumab (P) plus axitinib (A) versus sunitinib (S) for advanced renal cell carcinoma (RCC).2024 ASCO Abstract#4505.

[3]Yan XQ, Ye MJ, Zou Q, et al. Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study. Ann Oncol. 2024 Feb;35(2):190-199.

[4] "2024 Edition CSCO Renal Cell Carcinoma Diagnosis and Treatment Guidelines"

[5]Agarwal N, Azad AA, Carles J, et al . Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023 Jul 22;402(10398):291-303.

[6]Arun Azad, et al . Utility of ctDNA burden as a prognostic biomarker for efficacy in TALAPRO- 2: A phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).2024 ASCO Abstract#5020.

[7]Steven Yip, et al . Exploration of circulating tumor cell (CTC) conversion and CTC0 as prognostic biomarkers for efficacy in TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). 2024 ASCO Abstract#5023.

[8]Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008 Dec;102(11):1531-8.

[9]Sun Y, Xie L, Xu T, Jakobsen JS, et al. Efficacy and safety of degarelix in patients with prostate cancer: Results from a phase III study in China. Asian J Urol. 2020 Jul;7(3):301-308.

[10]Crawford ED, Shore ND, Moul JW, et al. Long-term tolerability and efficacy of degarelix: 5-year results from a phase III extension trial with a 1-arm crossover from leuprolide to degarelix. Urology. 2014;83(5):1122-1128.

[11]Powles TB, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase 3 study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). 2023 ESMO, LBA6.

[12]Shilpa Gupta, Patient-reported outcomes (PROs) from a randomized, phase 3 trial of enfortumab vedotin plus pembrolizumab (EV+P) versus platinum-based chemotherapy (PBC) in previously untreated locally advanced or metastatic urothelial cancer (la/mUC).2024 ASCO Abstract#4502.

*This article is organized by the medical community, and is only intended to provide scientific information to medical professionals for reference by healthcare professionals, and does not represent the views of this platform.

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