A Quick Recap from ASCO GU 2023: Prostate and Urothelial Cancer Highlights

The ASCO Genitourinary (GU) Cancers Symposium, which ended on February 18, 2023, was a three-day scientific and educational meeting designed to provide attendees with in-depth, multidisciplinary analysis of the timely topics in the study, diagnosis, and treatment of GU malignancies. DelveInsight has compiled the symposium’s major highlights so that one does not miss out on these expansions in GU malignancies, with a special focus on Prostate and Urothelial Cancer.

Major Pharma companies involved in presenting their Prostate and Urothelial cancer data readouts during the recent ASCO Genitourinary (GU) Cancers Symposium include BMS, Pfizer, Bayer, Janssen, AstraZeneca, and others.

Prostate cancer Highlights

• Talazoparib Plus Enzalutamide Improves rPFS in First-line metastatic castration-resistant prostate cancer (mCRPC)
• Niraparib Plus Abiraterone/Prednisone Maintains rPFS Benefit in HRR Gene-altered mCRPC
• Abiraterone/Olaparib Benefit is Sustained in Final OS Analysis for mCRPC
• Lutetium 177 PSMA-617 Following Radium-223 Is active and safe in mCRPC
• Darolutamide Plus ADT/Docetaxel Elicits Survival Benefit Across Subgroups in metastatic hormone-sensitive prostate cancer (mHSPC)

DelveInsight has explained a few of the abstracts below:

1. Positive findings from the Phase III TALAPRO-2 study in metastatic mCRPC patients (Abstract #LBA17)

Pfizer presented the trailblazing results from the Phase III TALAPRO-2 study of (NCT03395197) talazoparib in combination with enzalutamide in patients with mCRPC. It exists in the landscape of sequential and advancing studies of PARP inhibitors (PARPi) in prostate cancer. According to the primary analysis presented at the ASCO GU 2023 Conference, Pfizer mentioned that at a median follow-up of nearly 25 months in both arms, the primary endpoint of radiographic progression-free survival (rPFS) via blinded independent review demonstrated a 37% risk of progression or death in the patients receiving talazoparib and enzalutamide, with 151 events in the experimental and 191 events in the control arm. Although, the median rPFS was not reached in the combination arm (n = 402) compared with 21.9 months for patients in the placebo arm (n = 403). More importantly, patients with HRR-deficient mCRPC treated with talazoparib plus enzalutamide (n = 85) achieved a median rPFS of 27.9 months. In addition to that, the evaluable patients treated with talazoparib plus enzalutamide (n = 120) experienced an ORR of 61.7%, including a complete response (CR) rate of 37.5%, a partial response (PR) rate of 24.2%. Apart from that, the safety profile of the study was consistent. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were anemia (46.5%), low neutrophil (18.3%), and low platelet counts (7.3%). Furthermore, the US FDA has also granted a Priority Review for Pfizer’s supplemental new drug application (sNDA) for TALZENNA in combination with XTANDI for the treatment of men with mCRPC. The FDA’s decision on the sNDA is expected in 2023.

“We [saw] a consistent effect with talazoparib plus enzalutamide in prespecified subgroups, such as by age, performance status, Gleason score, site of metastasis, HRR status, or prior abiraterone [acetate (Zytiga)] or docetaxel.” – Expert opinion

2. Phase III MAGNITUDE study’s second intermediate analysis (IA2) of niraparib revealed encouraging results in mCRPC (Abstract #170)

Janssen announced the positive findings from the Phase III MAGNITUDE study (NCT03748641) of niraparib in combination with abiraterone acetate plus prednisone (AAP) as a first-line therapy in patients with BRCA-positive mCRPC. According to the analysis, at the cutoff date (June 17, 2022), after an additional 8 months of follow-up since the previous interim analysis, the median radiographic progression-free survival (rPFS) was 16.7 months in the niraparib group vs. 13.7 months in the placebo arm. Additionally, a trend toward overall survival (OS) improvement was observed in the BRCA subgroup, with a median of 29.3 months in the niraparib arm vs. 28.6 months in the placebo arm. Talking about safety, no new safety signals were identified. Regardless of causality, the most common adverse events for niraparib and AAP versus placebo and AAP were anemia, hypertension, and constipation. Patients without HRR gene alterations had no improvement in outcomes from using niraparib in combination with AAP. Further, the IA2 indicates that patients with BRCA mutations treated with niraparib and AAP experienced a trend toward delayed time to worst pain intensity and interference compared to placebo and AAP.

“These results continue to support genomic testing in metastatic CRPC, as well as the use of niraparib plus abiraterone in [patients with] HRR-positive metastatic CRPC, particularly those harboring BRCA gene alterations.” – Expert opinion

3. PROpel trial results of Olaparib benefits in 1L mCRPC (Abstract #LBA16)

According to the final findings from the prespecified overall survival (OS), analysis of the PROpel Phase III trial in mCRPC showed that at the final data cutoff date of October 12, 2022, LYNPARZA (olaparib) in combination with abiraterone and prednisone demonstrated median OS of 42.1 months versus 34.7 months for abiraterone plus placebo. This result represented a 7.4-month absolute difference in median OS versus a standard of care. However, the results presented were not so statistically significant, leading it to be the longest OS reported in a first-line Phase III trial in mCRPC, but the results support the combination of abiraterone plus olaparib as a new first-line treatment option for this patient population. The safety and tolerability of LYNPARZA plus abiraterone were in line with no new long-term safety issues identified. 

“The HRR-mutated cases are more effectively treated, but there is still a big effect in non–HRR-mutated or wild-type disease.” – Expert opinion

Delveinsight’s Analyst Opinion: Insights on the upward shift of PARP inhibitors in mCRPC:

PARP inhibitors are among the most promising therapeutic classes in the Phase III pipeline for mCRPC. Two PARP inhibitors, rucaparib, and olaparib received FDA approval in May 2020 for use in mCRPC harboring selected HRR aberrations after progression on at least one NAA therapy (olaparib) and at least one NAA and one chemotherapy (rucaparib). At present, the use of these agents is contingent upon the presence of aberrations in the HRR gene as identified on a commercial assay. Talazoparib (TALZENNA, Pfizer) and niraparib (ZEJULA, Janssen) (TALAPRO-2 and MAGNITUDE, respectively) are being investigated in combination with an AR-directed therapy for first-line treatment of mCRPC, similar to olaparib and rucaparib.

The results from the TALAPRO-2 study showed that adding talazoparib to the existing standard of care adds significant clinical benefit to the patients. In addition to delaying disease progression, this combination delayed prostate-specific antigen progression and time to chemotherapy without adversely influencing the patient’s quality of life. 

Patients with HRR-positive mCRPC, especially those with BRCA mutations, are likelier to experience poor outcomes. The positive findings of niraparib and abiraterone acetate plus prednisone overcome the poor prognostic outcome in these patients. In addition, these MAGNITUDE results underscore the importance of identifying patients with BRCA mutations to inform treatment strategies better and ensure the right patients receive add-on therapy with a PARP inhibitor. 

As the treatment landscape for prostate cancer continues to evolve, it can be anticipated that these innovative-targeted therapies could improve the outcomes for patients with HRR-positive prostate cancer. However, major competition could arrive in the first line of setting as; AstraZeneca and Merck’s powerhouse PARP inhibitor, Lynparza is now set for an upward movement into the first line treatment as its Phase III PROpel showed significantly delayed disease progression in all-comers in first-line mCRPC. In December 2022, the first PARP inhibitor (LYNPARZA), combined with abiraterone and prednisone, was approved in the European Union as the first-line treatment for patients with mCRPC. In the United States, the US FDA extended the PDUFA date by three months from December 2022 to March 2023 to provide further time for a full review of the sNDA for LYNPARZA in combination with abiraterone for the treatment of mCRPC. Therefore, watching the uptake and competition among the PARP inhibitor’s market share in the first-line setting would be interesting once each one gets launched in 2023/2024. Per Delveinsight’s estimates, we expect the four PARP inhibitors (Olaparib, Rucaparib, Talazoparib, and Niraparib) to reach a peak revenue of approximately USD 1.3 billion together in 2030 in the United States in first-line setting only.

Urothelial Cancer Highlights

• In first-line metastatic urothelial carcinoma, atezolizumab monotherapy is inadequate for overall survival.
• The benefit of sacituzumab govitecan is consistent following checkpoint inhibitor (CPI) in platinum-ineligible mUC.
• Nivolumab use as a standard of care in high-risk muscle-invasive urothelial carcinoma after radical resection is further supported by extended follow-up results of the Phase III CheckMate 274 research.
• enGene announces interim results from its Phase I/II LEGEND study of intravesical EG-70 (detalimogene voraplasmid) demonstrating a 71% CR rate at three months in patients with high-grade non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) that is BCG-unresponsive.

Assessment of the Key Abstracts in the Urothelial Cancer Market

Follow-up results of Nivolumab, the only immunotherapy successful as adjuvant therapy and a standard of care in high-risk muscle-invasive urothelial carcinoma following radical resection.

Bristol Myers Squibb (BMS) presented three-year follow-up results from the Phase III CheckMate -274 trial for the adjuvant treatment of patients with surgically resected, high-risk muscle-invasive urothelial carcinoma. In patients who underwent chemotherapy prior to surgery or are ineligible for chemotherapy, nivolumab remains the only immunotherapy and general medical treatment to reduce the risk of urothelial carcinoma recurrence after radical surgery. The FDA has already approved the drug for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy and adjuvant treatment of adult patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection of urothelial carcinoma.

The results were presented on the third day of the ASCO-GU 2023 symposium, with DFS (disease-free survival) as the primary endpoint. In the intent-to-treat (ITT) group, the 24-month and 36-month DFS rates for the nivolumab and placebo arms were 48.4% vs. 38.8% and 45.0% vs. 34.9%. The rates were 60.3% vs. 37.6% and 56.9% vs. 33.3%, respectively, in the PD-L1 population. Overall, 79% of patients in the nivolumab arm and 56% in the placebo arm of the study experienced any-grade treatment-related adverse effects (TRAEs), with 18% and 7%, respectively, reporting toxicities of Grade 3 or higher in the nivolumab and placebo arm, respectively.

“The durable follow-up results from CheckMate – 274 continue to fuel our excitement toward our ongoing research in earlier stages and its potential to change patient outcomes. We look forward to closely following the CheckMate – 274 trial, which is ongoing to assess additional key secondary endpoints, including overall survival to which we remain blinded.” -Expert opinion

Analyst Opinion: A significant trial for MIUC in its early stages was CheckMate-274. This research is the only one investigating adjuvant therapy for urothelial carcinoma that has achieved its primary endpoints and has been approved by the US FDA in August 2021. It should be noted that when comparing the efficacy outcomes from the initial report with a minimum follow-up of 5.9 months to the current presentation with a minimum follow-up of 31.6 months, the effect of adjuvant nivolumab vs. placebo is remarkably stable over time across primary, secondary, and exploratory endpoints. It is crucial to note that the outcome is with a specified duration of treatment—limited to 1 year of adjuvant therapy with long-lasting benefits. 

The trial is ongoing, and the data presented is not yet mature. In subgroups where the margins are narrower, particularly in patients who did not receive neoadjuvant chemotherapy or had PD-L1-negative tumors, it will be critical to see overall survival data before deciding whether to treat those patients with adjuvant therapy.