Revolutionizing Prostate Cancer Treatment: Insights from the COMBAT Phase II Trial on Bipolar Androgen Therapy

Study Overview

This study, titled "Bipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial," investigated the efficacy of bipolar androgen therapy (BAT) combined with nivolumab in treating metastatic castration-resistant prostate cancer (mCRPC) (1). The study was a multicenter, single-arm Phase 2 clinical trial, designated under the identifier NCT03554317. It enrolled 45 patients who had previously undergone extensive treatments for mCRPC. The intervention under investigation involved administering testosterone cypionate (400 mg intramuscularly every 28 days) as part of BAT, with the addition of nivolumab (480 mg intravenously every 28 days) after three cycles of BAT monotherapy.

The primary endpoint of the study was the confirmed PSA(50) response rate, which refers to a 50% or greater reduction in prostate-specific antigen (PSA) levels. This goal was achieved with an estimated response rate of 40% (18 out of 45 patients), significantly surpassing the 25% threshold set against the null hypothesis. Notably, 16 of these PSA(50) responses were observed prior to the addition of nivolumab. The study also evaluated several secondary endpoints, including the objective response rate (ORR), median PSA progression-free survival, radiographic progression-free survival (rPFS), overall survival (OS), and safety/tolerability of the treatment. The ORR was 24% (10 out of 42 patients), with three responses occurring after nivolumab was introduced. The median follow-up duration was 17.9 months, during which the median rPFS was recorded at 5.6 months and the median OS at 24.4 months.

In terms of safety, the BAT/nivolumab combination was well tolerated, with only five instances (11%) of drug-related, grade-3 adverse events. An exploratory analysis within the study showed that clinical response rates correlated with higher baseline levels of intratumoral PD-1+ T cells. Moreover, in patients who achieved a clinical response, BAT induced pro-inflammatory gene expression changes in paired metastatic tumor biopsies.

Standard Treatment

The current standard treatment for metastatic castration-resistant prostate cancer (mCRPC) typically involves a combination of androgen deprivation therapy (ADT) and other systemic treatments. The standard approach often includes:

  1. Second-Generation Anti-Androgens: Drugs such as enzalutamide or abiraterone acetate are commonly used. These drugs work by further lowering androgen levels or by blocking the androgen receptor, thereby inhibiting the growth of prostate cancer cells.

  2. Chemotherapy: Docetaxel is a frequently used chemotherapy agent for mCRPC, especially in patients who have a significant symptom burden or in whom hormonal therapies are no longer effective.

  3. Radiopharmaceuticals: Agents like radium-223 are used in certain cases, particularly for bone metastases.

  4. Immunotherapy: Sipuleucel-T, a cancer vaccine, is approved for use in certain cases of mCRPC.

  5. PARP Inhibitors: For patients with specific genetic mutations (like BRCA1/2), PARP inhibitors such as olaparib have shown efficacy.

  6. Bone-Modifying Agents: These are used to prevent skeletal-related events in patients with bone metastases.

The results of the COMBAT phase II trial investigating bipolar androgen therapy (BAT) combined with nivolumab are potentially impactful for several reasons:

  1. Novel Mechanism of Action: BAT represents a different approach by using high-dose testosterone, contrary to the traditional strategy of androgen deprivation. This could open new avenues for treatment, especially for patients who have become resistant to standard therapies.

  2. Combination with Immunotherapy: The addition of nivolumab, an immune checkpoint inhibitor, to BAT is innovative. This study suggests that BAT might augment the immune response against tumor cells, which can be further enhanced by immunotherapy.

  3. Response Rates and Survival Data: The observed PSA(50) response rate and the objective response rates, along with the data on progression-free survival and overall survival, are promising, especially considering that the study population consisted of heavily pretreated patients.

  4. Safety and Tolerability: The combination therapy was well-tolerated, an important consideration in a patient population that often deals with multiple comorbidities and the side effects of prolonged cancer treatment.

  5. Biomarker Correlation: The correlation of treatment response with baseline levels of intratumoral PD-1+ T cells and pro-inflammatory gene expression changes offers potential biomarkers for identifying patients who might benefit most from this treatment.

In summary, while these results are promising and represent a potentially significant advancement in mCRPC treatment, it's important to note that this was a Phase 2 trial. Larger, randomized Phase 3 trials are necessary to confirm these findings and to compare the BAT plus nivolumab regimen directly against current standard treatments. If future studies corroborate these results, this combination therapy could become an important addition to the treatment arsenal for mCRPC.

Clinical Impact Potential

The clinical impact potential of the COMBAT phase II trial can be assessed as medium. This assessment is based on several factors:

  1. Promising Results in a Tough-to-Treat Population: The trial showed encouraging results in a population of heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) patients. Achieving a 40% PSA(50) response rate and a 24% objective response rate in this group is notable, considering the limited efficacy of current treatment options in such advanced stages.

  2. Novel Therapeutic Approach: The trial's approach of combining bipolar androgen therapy (BAT) with an immune checkpoint inhibitor (nivolumab) introduces a novel mechanism of action in the treatment of mCRPC. This combination therapy, which differs from the traditional androgen deprivation strategy, could provide a new avenue for treatment, especially for patients who have developed resistance to current therapies.

  3. Safety Profile: The treatment was well-tolerated with a relatively low incidence of severe adverse events. This is crucial in the context of mCRPC, where patients often have multiple comorbidities and might have experienced significant side effects from previous treatments.

However, there are also reasons to be cautious in assessing the trial's impact:

  1. Early Phase of Research: The trial is a Phase 2 study. While the results are promising, they need to be validated in larger, randomized Phase 3 trials to better understand the efficacy and safety of this treatment approach compared to standard therapies.

  2. Lack of a Control Group: As a single-arm study, it lacks a control group for direct comparison. This makes it challenging to definitively conclude the superiority or equivalence of this treatment approach over current standard treatments.

  3. Biomarker Limitations: The study identifies potential biomarkers related to treatment response (like intratumoral PD-1+ T cells), but these findings need further validation. Biomarkers play a critical role in personalizing treatment and predicting response.

  4. Generalizability: The results might not be generalizable to all patients with mCRPC, especially those with different disease characteristics or those who have not been heavily pretreated.

In conclusion, the medium impact assessment reflects the balance between the trial's promising results and innovative approach, and the need for further research to confirm these findings and establish the therapy's place in the treatment landscape for mCRPC.

Reference

Markowski MC, Taplin ME, Aggarwal R, Sena LA, Wang H, Qi H, Lalji A, Sinibaldi V, Carducci MA, Paller CJ, Marshall CH, Eisenberger MA, Sanin DE, Yegnasubramanian S, Gomes-Alexandre C, Ozbek B, Jones T, De Marzo AM, Denmeade SR, Antonarakis ES. Bipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial. Nat Commun. 2024 Jan 2;15(1):14. doi: 10.1038/s41467-023-44514-2. PMID: 38167882; PMCID: PMC10762051.