Paul Sieber, MD, medical director, Clinical Trials, Keystone Urology, discusses the importance of evaluating comorbidities in patients with prostate cancer, including assessing risk factors for cardiovascular events in those who are initiating androgen deprivation therapy (ADT).

At the 2023 AUA Annual Meeting, investigators presented data from a claims-based study with the goal of evaluating cardiovascular events in patients with prostate cancer who are being treated with ADT. Notably, investigators watched for patients who had 1 or more of these 3 common comorbidities: diabetes mellitus, hypertension, and hyperlipidemia. Furthermore, investigators included patients who had begun ADT a minimum of 12 months prior to study enrollment and continued ADT for at least 6 months after. It was found that 7.6% of patients with only hypertension experienced cardiovascular events following ADT; 7.3% of patients with only hyperlipidemia experienced cardiovascular events after ADT; and 9.9% of patients with both hypertension and hyperlipidemia had cardiovascular events following ADT. Furthermore, 14.4% of patients who experienced a cardiovascular event post-ADT initiation had only diabetes, and patients with all 3 of these comorbidities had a 16.1% risk of a cardiovascular event after starting ADT.

When urologists treat patients with prostate cancer, they should pay close attention to patient comorbidities, Sieber begins. Although oncologists are mindful of some comorbidities, such as old age, some do not recognize comorbidities as often as necessary, and should also pay closer attention to the projected lifespan of these patients, he explains. Because of these unmet needs, it is important to aim to better understand patient comorbidities when making treatment recommendations, Sieber says. This is an easy first step in recognizing this vital topic, Sieber emphasizes.

Although investigators have identified that patients with prostate cancer who receive ADT are at risk for cardiovascular events, the next steps for addressing this issue are unclear, Sieber notes. For instance, it is unknown whether a cardiac calcification score is enough to assess patient risk, or whether patients need a stress test, Sieber explains. Moving forward, it is important to establish a standard for assessing the risk for cardiovascular events in this population, he concludes.

Videos

Paul Sieber, MD, discusses the importance of evaluating comorbidities in patients with prostate cancer, including assessing risk factors for cardiovascular events in those who are initiating androgen deprivation therapy.


Dr Sieber on the Importance of Evaluating Comorbidities in Prostate Cancer Prior to ADT

Paul Sieber, MD, medical director, Clinical Trials, Keystone Urology, discusses the importance of assessing risk factors for cardiovascular events in patients with prostate cancer who are initiating androgen deprivation therapy (ADT).

A claims-based study, findings from which were presented at the 2023 AUA Annual Meeting, aimed to evaluate the likelihood of cardiovascular events in patients with prostate cancer who are receiving ADT and who have 1 or more of 3 common comorbidities: diabetes mellitus, hypertension, and hyperlipidemia.

This study included patients with prostate cancer who began ADT at least 12 months before enrollment and continued ADT for at least 6 months after enrollment. Patients were stratified by baseline comorbidity. Cardiac events, including stroke, myocardial infarction, unstable angina, thromboembolism, the need for coronary artery bypass graft, and the need for percutaneous coronary intervention were assessed in these patients for a maximum of 3 years after starting ADT.

In total, 7.6% and 7.3% of patients with only hypertension or hyperlipidemia, respectively, experienced cardiovascular events after ADT initiation, and 9.9% of patients with both hypertension and hyperlipidemia had a cardiovascular event. Additionally, 14.4% of patients with only diabetes experienced a cardiovascular event post-ADT initiation. However, patients who had all 3 comorbidities had the highest risk for a cardiovascular event after starting ADT; 16.1% of these patients experienced a cardiovascular event, with a hazard ratio of 2.15.

These findings can inform decision making regarding whether a patient with prostate cancer should receive ADT, Sieber says. If a patient being considered for ADT is receiving medication for hypertension, hyperlipidemia, and diabetes mellitus, they likely need a cardiac consultation, Sieber emphasizes. Although cardiac consultations are typically reserved for patients who need clearance for surgery, such as a radical prostatectomy, cardiac clearances may also be important for patients being considered for ADT, Sieber concludes.

Paul Sieber, MD, discusses the importance of assessing risk factors for cardiovascular events in patients with prostate cancer who are initiating androgen deprivation therapy. 

Dr Sieber on Comorbidities and the Risk of Cardiovascular Events in Prostate Cancer

Sipuleucel-T (Provenge) received an FDA approval in 2010 and a subsequent CMS coverage decision in 2011. At Lancaster Urology in Pennsylvania, we began infusing sipuleucel-T in 2011, and at the 7-year mark, we conducted a review to evaluate these first years of therapy. We had complete information on 94 patients.

Sipuleucel-T is for first-line therapy for men with metastatic castration-resistant prostate cancer (mCRPC) who are asymptomatic or have minimal symptoms, and it is now incorporated into treatment guidelines issued by the American Urological Association, European Association of Urology, and National Comprehensive Cancer Network.

 excluded men with visceral metastasis, although the guidelines now recommend sipuleucel-T for this population. Many papers have been written since the agent’s 2010 approval, but the patient cohorts have tended to be small. In addition, papers have tried to address the plethora of new treatments and how they might be best sequenced, layered, and used cost-effectively.

 This review was undertaken to see how our practice has addressed all this information in the management of men with mCRPC. In addition, we hoped to gain insights into our survival outcomes.

Table 1. Survivorship Following Treatment With Sipuleucel-T

We reviewed all patients treated with sipuleucel-T over a 7-year period at a busy community urology practice. The patients were categorized by year of sipuleucel-T treatment, prostate-specific antigen (PSA) at time of therapy, subsequent therapies, and overall survival. As 

 illustrates, most of these men were alive at the time of this review. The median age was 74. Roughly 70% of men with a PSA <22.1 were alive at the time of this review.

The majority received sipuleucel-T in the past 4 years, partly because of an improved understanding of the optimal patient for this therapy (

). Although survival appears shorter in recent years, the majority of men treated since 2016 were alive at the time of this review (

). The patients were placed into PSA quartiles, as previously described from the original trials.

 Again, the majority of men in the favorable lowest quartile remained alive at the time of this review.

Finally, we addressed the addition of other therapies and their impact on overall survival. Most men went on to receive additional therapies. At the time of this review, several patients were still on their first or second therapy following sipuleucel-T.

Table 3. Survival Results According to PSA Quartiles

The incorporation of sipuleucel-T in the management of mCRCP has gradually changed in our practice since the agent received FDA approval, and its use continues to rise. Because we are seeing stage migration in prostate cancer, as are others,

 we feel the incidence of metastatic prostate cancer will continue to increase. The first article to better address the timing of sipuleucel- T came from Schellhammer et al.

 The authors looked at the original pivotal trials with sipuleucel-T and found that the PSA level at treatment was exceedingly important. They sorted patients into quartiles based on PSA at the time of sipuleucel-T administration. The hazard ratio for those patients with a PSA <22.1 (the lowest quartile) was a striking 0.51 compared with a PSA >134 (highest quartile) hazard ratio of 0.84. This translated into a median survival improvement of 13 months for the lowest quartile. In addition, performance status, increased tumor burden, and PSA doubling time appear to predict for more rapid deterioration after sipluleucel-T.

 Thus, we have moved to earlier administration of sipuleucel-T in regard to PSA at time of administration, more prolonged PSA doubling times, and better performance status. These 3 factors are helpful in identifying the ideal patient for immunotherapy with sipuleucel-T. It is encouraging that we are seeing longer survivals post administration of sipuleucel- T, as this lends credence to these measures for patient selection.

The majority of patients receiving sipuleucel-T have also gone on to 1 or more therapies. Both timing and layering have continued to evolve,

 but this has not been without setbacks. The first trials combining radium-223 (Xofigo) and abiraterone (Zytiga) versus radium-223 alone were halted and led to a warning from the manufacturer against combination therapy after an increase in bone fractures and deaths was noted in the combination arm of the study.

 Multiple studies have been completed and are ongoing looking at combination therapy with sipuleucel-T. Small et al looked at the combination with abiraterone and found no evidence of vaccine production interference as measured by cumulative antigen presenting cells number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) suggested no interference from concurrent use of abiraterone acetate plus prednisone.

 Scholz et al have looked at adding additional immunotherapy with ipilimumab with some success.

 Finally, Antonarakis et al have looked at administration of sipuleucel-T prior to androgen deprivation therapy in men. with biochemically recurrent prostate cancer who are at high risk for metastasis.

Present guidelines suggest the sequential use of agents post sipuleucel-T. Our experience with sequential therapy has been very positive, with most patients having received multiple therapies. Many of our patients have received sipuleucel-T in the past 3 years and are only on their first or second subsequent therapies, and we assume most will receive second and third, even fourth, lines of therapy. We have already noted that patients who receive multiple lines of therapy seem to have the longest survival. We hope to see ongoing extensions in survival as we move to the ideal patient for sipuleucel-T and better understand how to sequence the multiple options now available. Most likely, this will continue to rapidly evolve with the multitude of new agents being tested in castration-resistant cancer.

The management of mCRPC continues to evolve. As we continue to add new agents, new ideas about the sequencing and of layering of therapies will undoubtedly develop. We have seen our early findings with sipuleucel-T appear consistent with what other authors have reported. We are seeing median survivals for patients with mCRPC extending well beyond the results of multiple single-agent clinical trials

We continue to follow the current guidelines, placing sipuleucel-T first in the treatment algorithm in asymptomatic patients with mCRPC. We believe we have been successful in identifying the optimal patient for immunotherapy. The use of additional layers of therapy is now routine and most likely will continue to evolve, hopefully, with the addition of new novel agents.

NCCN Clinical Practice Guidelines in Oncology—Prostate Cancer. Version 2.2019. National Comprehensive Cancer Network website. nccn.org/ professionals/physician_gls/pdf/prostate_blocks.pdf. Updated April 24, 2019. Accessed July 24, 2019.

Castration-resistant prostate cancer (2018). American Urological Association website. auanet.org/guidelines/prostate-cancer-castration-resistant- guideline. Published 2013. Updated 2018. Accessed July 24, 2018.

Cornford P, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIUG guidelines on prostate cancer. part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. 

. 2017;71(4);630-642. doi: 10.1016/j.eururo.2016.08.002.

Kantoff P, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel- T immunotherapy for castration-resistant prostate cancer. 

. 2010;363(5):411-422. doi: 10.1056/NEJMoa1001294.

Crawford ED, Petrylak DP, Shore N, et al; Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR II) Group. The role of therapeutic layering in optimizing treatment for patients with castration-resistant prostate cancer (prostate cancer radiographic assessments for detection of advanced recurrence II). 

. 2017;104:150- 159. doi: 10.1016/j.urology.2016.12.033.

Zheng H, Chen J, Qiu W, et al. Safety and efficacy of first-line treatments for chemotherapy-naïve metastatic castration-resistant prostate cancer: a systematic review and indirect comparison. 

. 2017;3941217. doi: 10.1155/2017/3941217.

Grochtdreis T, König HH, Dobruschkin A, von Amsberg G, Dams J. A cost-effectiveness analyses and cost analyses in castration-resistant prostate cancer: a systematic review. 

. 2018;13(12):e0208063. doi: 10.1371/journal.pone.0208063.

Nuhn P, De Bono J, Fizazi K, et al. Update on systemic prostate cancer therapies: management of metastatic castration-resistant prostate cancer in the era of precision oncology. 

. 2019;75(1):88-99. doi: 10.1016/j. eururo.2018.03.028.

Schellhammer P, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. 

. 2013;81(6):1297- 1302. doi: 10.1016/j.urology.2013.01.061.

Caram M, Estes J, Griggs JJ, Lin P, Mukherjee B. Temporal and geographic variation in the systemic treatment of advanced prostate cancer. 

. 2018;18(1):258. doi: 10.1186/s12885-018-4166-3.

Reese AC, Wessel SR, Fisher SG, Mydlo JH. Evidence of prostate cancer “reverse stage migration” toward more advanced disease at diagnosis; data from the Pennsylvania Cancer Registry. 

. 2016;34(8):335. e21-8. doi: 10.1016/j.urolonc.2016.03.014.

Wei XX, Perry J, Chang E, et al. Clinical variables associated with overall survival in metastatic castration-resistant prostate cancer patients with sipuleucel-T immunotherapy. 

. 2018;16(3):184-190.e2. doi: 10.1016/j.clgc.2017.12.004.

Bilen M, Hess K, Subudhi SK, et al. Clinical predictors of survival in patients with castration-resistant prostate cancer receiving sipuleucel-T cellular immunotherapy. 

. 2017;80(3):583- 589. doi: 10.1007/s00280-017-3391-9.

Smith M, Parker C, Tombal BF, et al. ERA223: a phase 3 trial of radium-223 dichloride in combination with abiraterone and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve patients with bone dominant metastatic castration-resistant prostate cancer. 

. 2017;34(suppl 15). doi: 10.1200/JCO.2016.34.15_suppl.TPS5088.

Small E, Lance R, Gardner TA, et al. A randomized phase II trial of sipuleucel- T with concurrent versus sequential abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer. 

. 2015;21(17):3862-3869. doi: 10.1158/1078-0432.CCR-15-0079.

Scholz M, Yep S, Chancey M, et al. Phase I clinical trial of sipuleucel-T combined with escalating doses of ipiluminab in progressive metastatic castrate-resistant prostate cancer. 

. 2017;6:11-16. doi: 10.2147/ITT.S122497.

Antonarakis ES, Kibel AS, Yu EY, et al; STAND Investigators. Sequencing of sipuleucel-T and androgen deprivation therapy in men with hormone-sensitive biochemically recurrent prostate cancer: a phase II randomized trial. 

. 2017;23(10):2451-2459. doi: 10.1158/1078-0432. CCR-16-1780.

Articles

Sipuleucel-T received an FDA approval in 2010 and a subsequent CMS coverage decision in 2011. At Lancaster Urology in Pennsylvania, we began infusing sipuleucel-T in 2011, and at the 7-year mark, we conducted a review to evaluate these first years of therapy.

Where Sipuleucel-T Fits in the Treatment of mCRPC

Paul Sieber, MD, principal investigator for clinical trials with Lancaster Urology, talks about the CHAARTED trial, which examines chemohormonal therapy versus androgen ablation for extensive disease in prostate cancer.

The study looked at patients that have received no previous treatment., Siebar says. During the trial, half the patients received standard hormonal therapy while the other half received standard hormonal therapy plus 6 cycles of docetaxel. Sieber says patients with both high-volume metastasis and low-volume disease were included in the study.

Findings over a period of years showed the survival advantage was about 17 months in the group that had high-volume metastatic disease. These results could change how patients with metastatic disease are treated initially, says Sieber. However, there is some controversy surrounding CHAARTED because the data is limited and similar studies have had differing findings.

Dr. Sieber on the CHAARTED Trial

Paul R. Sieber, MD, Urological Association of Lancaster, explains that the initial burst of activity following the introduction of androgen-deprivation therapy (ADT) is severe and may result in as much as a 10% loss in bone density. To add perspective, he notes that this degree of bone loss is 3 to 5 times what is lost during menopause in women.

Bone loss may continue in men as they continue to receive ADT, which makes managing and controlling bone health extremely important.

A number of agents are available to help manage bone health for prostate cancer patients. Sieber notes that the only agent with a direct FDA approval in prostate cancer is denosumab, a monoclonal antibody that binds to RANK ligand. Other agents, such as zoledronic acid (Zometa) and bisphosphonates are approved to treat bone metastases, but Sieber believes denosumab is superior to these agents.

Dr. Paul Sieber, from the Urological Association of Lancaster, on Managing Bone Health After the Introduction of ADT.

Paul R. Sieber, MD

Articles

Dr Sieber on the Importance of Evaluating Comorbidities in Prostate Cancer Prior to ADT

Dr Sieber on Comorbidities and the Risk of Cardiovascular Events in Prostate Cancer

Where Sipuleucel-T Fits in the Treatment of mCRPC

Dr. Sieber on the CHAARTED Trial

Dr. Sieber on Managing Bone Health After ADT