On the Horizon for Metastatic Castration-Resistant Prostate Cancer:Dr Madan Discusses Two New Therapies
Presenter
Ravi Madan, MD
Conference
2024 ASCO Direct™ Philadelphia
Background
Metastatic, castration-resistant prostate cancer (mCRPC) is a challenging stage of disease wherein prostate tumors, which are normally dependent on hormonal signaling for their growth, have adapted mechanisms to proliferate despite the use of hormonal therapy (typically inhibitors of the androgen receptor [AR] pathway). While newer treatments such as prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical agents (e.g., Lutetium PSMA-Lu177) have improved patient outcomes in mCRPC, there is a demand for additional therapeutic options that can effectively target these treatment-resistant cancers with minimal toxicity. Findings presented at this year’s Annual Meeting of the American Society of Clinical Oncology (ASCO) reported preliminary efficacy for 2 new treatments in mCRPC, as highlighted by Dr Ravi Madan in his presentation from the ASCO Direct™ Philadelphia Conference.
Phase I Trial Results: JNJ-6420
The first abstract detailed early stage (phase I) results for JNJ-6420, a radioactive actinium225–labeled radiopharmaceutical agent which targets a protein called human kallikrein 2 (hK2). hK2 is a protein related to prostate specific antigen (PSA) which is overexpressed in prostate cancer cells. Upon binding of JNJ-6420 to hK2 on the cell surface, the drug becomes internalized and releases its radioactive payload into the cell, causing cell death.
This phase 1 trial evaluated JNJ-6420 in mCRPC patients, most of whom had previously undergone chemotherapy and other standard treatments for their advanced disease. Patients received different doses of JNJ-6420, with adjustments based on tolerance and initial response. The primary objectives were to assess safety, determine the maximum tolerated dose, and observe any tumor responses (as assessed by PSA reductions).
Results presented at ASCO 2024 showed that many patients in the study experienced notable reductions in PSA levels, indicating that JNJ-6420 effectively targeted prostate cancer cells. A significant number of patients also had durable reductions in their PSA, suggesting sustained anti-cancer activity. Dr Madan noted that PSA reductions were maintained over time in several patients, with some showing prolonged tumor control and he noted this was particularly encouraging for a heavily pretreated population.
The most common side effects of JNJ-6420 included blood cell count reductions, particularly mild-to-moderate neutropenia and thrombocytopenia, which were overall manageable. A unique side effect observed was mild interstitial lung disease (ILD) in a few patients, which Dr Madan noted was an uncommon finding with prostate cancer radiopharmaceuticals. Another noteworthy adverse effect he noted was dry mouth, which could possibly be related to the expression of the drug target, hK2, in normal salivary glands.
Overall, Dr. Madan thought that JNJ-6420 represented an exciting new approach for targeting mCRPC with radiopharmaceuticals, especially given its favorable safety profile and the evidence for durable responses. While noting the need for additional studies to clarify JNJ-6420’s position in mCRPC treatment, he emphasized that this trial opens the door to more advanced radiopharmaceuticals that might be combined with existing therapies. Dr. Madan also raised key questions about how multiple radiopharmaceuticals (including the previously approved radiopharmaceutical agent, lutetium PSMA-Lu177) might be used together or in sequence in order to prolong treatment and maximize efficacy in mCRPC.
Phase I/II Trial Results for the ARV-766 (PROTAC) Trial in mCRPC
A second abstract detailed findings from the phase I/II trial of ARV-766, a PROteolysis TArgeting Chimera (PROTAC) designed to degrade androgen receptors. Prostate cancer growth is often driven by the androgen receptor (AR), which remains active even after androgen deprivation therapy in mCRPC. Androgen receptor pathway inhibitors (ARPIs) can lose their effectiveness over time due to androgen receptor mutations, such as the AR-V7 splice variant, that allows cancer cells to overcome these treatments. ARV-766 is a PROTAC that selectively degrades AR proteins, disrupting the receptor’s function and potentially providing a more comprehensive treatment approach for resistant prostate cancers.
The ARV-766 trial enrolled mCRPC patients who had previously been treated with ARPIs and, in many cases, chemotherapy for their advanced disease. Patients were administered varying doses of ARV-766, with close monitoring for PSA response and safety outcomes. The primary goals of this early stage study were to assess safety, determine the optimal dose, and evaluate preliminary efficacy. Findings from the trial reported at ASCO 2024 showed that many patients exhibited significant PSA reductions, a positive signal that ARV-766 effectively targets the AR pathways even in patients with resistant mCRPC. The treatment response was particularly notable in patients with AR-V7 mutations. In addition, several patients maintained PSA reductions over extended periods, suggesting that ARV-766 has the potential for lasting efficacy. ARV-766 was generally well-tolerated, with low rates of serious adverse events. The most common side effects were mild fatigue and nausea, with very few patients experiencing severe toxicities. Importantly, no dose-limiting toxicities were observed, indicating a favorable safety profile that supports further investigation of this agent.
Dr. Madan highlighted that ARV-766 offers a promising approach for patients with advanced mCRPC who may have limited treatment options due to AR mutations. The drug’s mechanism as a PROTAC allows it to degrade androgen receptors directly, which could be beneficial for tumors resistant to traditional ARPIs. Dr. Madan expressed optimism about ARV-766’s potential and noted that continued research may help better define its role as a component of combination regimens or as a second-line therapy for patients with mCRPC.
Speaker Disclosure Information: Dr Madan reported no relevant disclosures for this presentation.