PLUVICTO is an intravenous radioligand therapy (RLT) combining a targeting compound (a ligand) with a therapeutic radionuclide (lutetium-177 in this case). After administration into the bloodstream, PLUVICTO binds to target cells, including prostate cancer cells that express PSMA, a transmembrane protein.

During the ongoing ESMO 2023, Novartis shared findings from the Phase III PSMAfore trial. This study evaluated the effectiveness and safety of PLUVICTO in comparison to switching androgen receptor pathway inhibitors (ARPIs) such as ZYTIGA or XTANDI. The focus was on patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) who had not undergone a taxane-containing treatment. Additionally, participants were required to have experienced progression after only one round of a second-generation ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide).

Data presented showed that PLUVICTO met its primary endpoint with a clinically meaningful and statistically significant benefit in rPFS.

PLUVICTO successfully achieved its primary endpoint of radiographic progression-free survival (rPFS) at the primary analysis, utilizing centrally confirmed rPFS events with data cut off in October 2022. However, the subsequent exploratory rPFS analysis, incorporating the latest data cut off in June 2023, only showed nominal significance. The trial will persist in evaluating overall survival (OS), with the next interim OS analysis anticipated in 2024.

Regarding adverse events (AEs), the PLUVICTO group exhibited 77 Grade 3-4 AEs (33.9%), while the ARPI change group reported 100 (43.1%). In terms of serious AEs, the PLUVICTO group recorded 46 cases (20.3%) compared to 65 (28.0%) in the ARPI change group. AEs leading to dose adjustment were observed in 8 instances (3.5%) in the PLUVICTO group and 35 in the ARPI change group. Common AEs affecting at least 10% of patients in either group included dry mouth, asthenia, nausea, anemia, fatigue, constipation, decreased appetite, arthralgia, COVID-19, diarrhea, back pain, vomiting, peripheral edema, and weight loss.

A progress of more than 50% in progression-free survival is typically a reason for celebration in the field of oncology. However, PLUVICTO's results were somewhat subdued due to a worrisome indication related to the life expectancy of patients.

Contrary to the significant tumor progression observed, the use of PLUVICTO in PSMAfore was associated with a 16% elevated risk of mortality. The overall survival results are complicated by the fact that 84% of patients in the control arm, whose disease progressed, eventually received PLUVICTO. Upon adjusting for crossover treatments, PLUVICTO demonstrated a 20% reduction in the risk of death compared to the control group.

The extensive crossover patient population essentially turns the overall survival analysis into a comparison between pre-taxane PLUVICTO and the subsequent use of radiotherapy, although this sequencing scenario was not prospectively designed for testing. PLUVICTO already has FDA approval as a later-line post-taxane therapy. Therefore, the crossover-adjusted analysis is more of a calculated measure that does not mirror real-world practice, despite being the pre-specified method for overall survival in PSMAfore.

The recent overall survival data stems from the second interim analysis of PSMAfore. The trial initially met its primary endpoint at the first interim analysis with a 59% reduction in the risk of progression or death compared to the control after a median follow-up of 7.3 months. However, Novartis delayed filing for approval as the FDA sought a more mature overall survival analysis, as a negative trend in overall survival is a significant concern for regulatory approval. While the current readout does not necessarily imply that PLUVICTO caused harm, the potential for a detrimental impact on patient survival is not typically tolerated by the FDA. Consequently, the company now plans to submit for approval in 2024, a delay from the initial target by the end of 2023.

KOL insights

“In summary, PSMAfore met the primary rPFS end point with a very favorable adverse event profile, in taxane-naive patients with metastatic CRPC.”– MD, United States.

Conclusion

PLUVICTO demonstrated an improvement in radiographic progression-free survival (rPFS) compared to ZYTIGA or XTANDI in metastatic castration-resistant prostate cancer (mCRPC) patients. These individuals were taxane-naïve and had experienced disease progression on a prior second-generation androgen receptor pathway inhibitor (ARPI), achieving the primary endpoint of Phase III PSMAfore trial. However, mixed survival data from the study focusing on PLUVICTO in earlier-stage prostate cancer has led to a slower regulatory timeline. Findings presented at ESMO 2023 indicated that patients initially assigned to PLUVICTO in the trial might not have a longer lifespan than those receiving hormone therapies. Yet, patients in the hormone therapy arm who “crossed over” to receive PLUVICTO treatment upon disease progression influenced these results.

Novartis holds a positive outlook regarding the market potential of PLUVICTO, given its success in generating over USD 270 million in the United States in 2022 within its currently approved setting in the very first year of its launch. As per Delveinsight’s estimates, considering a fast uptake of the radioligand therapy, PLUVICTO is estimated to generate approximately USD 1.4 billion in the third-line setting, whereas if approved in earlier line, it can add approximately USD 500 million by 2032 in the United States alone.

Even though the company faces challenges due to prolonged manufacturing issues that could impact its plans, the positive outlook relies on favorable overall survival results from the PSMAfore trial in 2024 and another Phase III trial, PSMAaddition, which is expected to release data next year for metastatic hormone-sensitive prostate cancer (mHSPC/mCSPC). To prepare for the potential expansion of PLUVICTO and broader radiotherapy initiatives, Novartis is actively enhancing its production capabilities. This includes increasing capacity at its radioligand site in Millburn, New Jersey, following recent manufacturing challenges and a temporary production halt.

As per DelveInsight’s estimates, in 2022, the total prevalent population of mCRPC was around ~128,000, respectively in the 7MM. For more insight into the Prostate cancer types including metastatic CRPC, metastatic CSPC, non-metastatic CRPC, and non-metastatic CSPC, their respective geographical patient burden, treatment, and changing market landscape-related advancements, refer to these reports:

• Metastatic Prostate Cancer Market Insight and Market Forecast
• Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Market Insight and Market Forecast
• Non-metastatic Prostate Cancer (nmPC) Market Insight and Market Forecast
• Metastatic Castration-Resistant Prostate Cancer (mCRPC) Market Insight and Market Forecast