Rahul Aggarwal, MD, associate director for Clinical Sciences, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, associate professor of hematology/oncology, UCSF, discusses key findings from a phase 2a trial (NCT03910660) evaluating the combination of BXCL701 and pembrolizumab (Keytruda) in patients with metastatic castration-resistant prostate cancer (mCRPC) with the small cell neuroendocrine cancer (SCNC) phenotype.

De novo and treatment-emergent SCNC mCRPC is associated with poor survival outcomes. BXCL701 operates by activating innate immunity and adaptive immunity leading to cancer cell death. The oral agent was evaluated at a twice-daily dose of 0.3 mg on days 1 through 14 of each 21-day cycle in combination with 200 mg of intravenous pembrolizumab given once every 3 weeks.

The primary end point of the trial was composite response rate, which comprised the objective response rate (ORR) in patients with measurable disease per RECIST v1.1 criteria, circulating tumor cell (CTC) conversion from at least 5/7.5 mL to less than 5/7.5 mL, and at least a 50% reduction in prostate-specific antigen (PSA50) from baseline. Among the 34 patients enrolled to the phase 2a cohort, 28 were evaluable and 25 were evaluable per RECIST v1.1 criteria. In this population, the composite response rate was 25% and the ORR was 20% (n = 5). Of the 5 responders, 4 had received prior platinum-based chemotherapy.

Notably, the median duration of response was more than 6 months (range, 1.3-17.4). Several additional responders were identified when investigators evaluated responses including CTC and PSA50, leading to a composite ORR of 25%, Aggarwal says. Investigators are encouraged by this efficacy signal in this heavily pretreated population with aggressive disease biology who had received a median of 3 (range, 1-8) prior lines of therapy. 

The safety profile of the combination was also evaluated, and proved to be manageable, Aggarwal says. Forty-seven percent (n = 16) and 3% (n = 1) of patients experienced a grade 3 and 5 treatment-emergent adverse effect (AE), respectively. The addition of pembrolizumab to BXCL701 did not result in a significant increase in immune-related AEs, with only 1 case of grade 3 colitis having occurred. Moreover, cytokine release, hypotension (grade 3, n = 2), and hypoxia were largely grade 1 and 2 and did not lead to treatment discontinuation, Aggarwal concludes.

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Rahul Aggarwal, MD, discusses key findings from a phase 2a trial evaluating the combination of BXCL701 and pembrolizumab in patients with metastatic castration-resistant prostate cancer with the small cell neuroendocrine cancer phenotype.

Dr Aggarwal on the Activity of BXCL701 Plus Pembrolizumab in SCNC mCRPC

Rahul Aggarwal, MD, associate director for Clinical Sciences, University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, associate professor of hematology/oncology, UCSF, discusses the association between baseline characteristics and prostate-specific antigen (PSA) progression-free survival (PFS) in patients with high-risk biochemically relapsed prostate cancer from the phase 3 PRESTO trial (NCT03009981).

The study evaluated androgen-deprivation therapy (ADT) plus apalutamide (Erleada) with or without abiraterone acetate (Zytiga) and prednisone vs ADT alone. In a post-hoc analysis presented at the 2023 Genitourinary Cancers Symposium, findings showed that a Gleason score of 9 or 10 was associated with shorter PSA PFS following a finite duration of treatment given for biochemically recurrent prostate cancer.

Primary results from PRESTO were reported at the 2022 ESMO Congress

, which showed that apalutamide plus ADT elicited a median PSA PFS of 24.9 months (95% CI, 23.3-32.3), compared with 20.3 months (95% CI, 18.2-22.9) with ADT alone. However, the further addition of abiraterone and prednisone to the apalutamide/ADT regimen did not significantly boost clinical outcomes.

Patients who have a short PSA doubling time of 9 months or less are the patients at the highest risk for development of distant metastases, Aggarwal notes. Investigators aimed to address if it was more beneficial to intensify hormone therapy or give it for a finite treatment period to prolong the time until the PSA rises once patients stop therapy, Aggarwal adds.

In the post-hoc analysis, investigators examined baseline characteristics across all 3 arms to examine what was associated with the best outcomes, Aggarwal continues. PSA doubling time is classically considered one of the strongest prognostic features; however, a baseline Gleason score of 9 or 10 was associated with shorter PSA PFS, Aggarwal says. Notably, Gleason score was obtained from a sample that was obtained, on average, 4 years before a patient entered the study, meaning that biology is still relevant to outcomes with hormone therapy in this setting, Aggarwal adds.

Conversely, investigators did not see a difference in PSA PFS with respect to PSA doubling time of less than 3 months vs 3 to 9 months, prior radiation, and the time interval from radical prostatectomy to study entry, Aggarwal concludes.

Rahul Aggarwal, MD, discusses the association between baseline characteristics and prostate-specific antigen progression-free survival in patients with high-risk biochemically relapsed prostate cancer from the phase 3 PRESTO trial.

Dr. Aggarwal on Characteristics Associated With PSA PFS from the PRESTO Trial in Prostate Cancer

Rahul Aggarwal, MD, developmental therapeutics specialist, genitourinary oncologist, the University of California Health (UCSF), UCSF Helen Diller Family Comprehensive Cancer Center, discusses the rationale for investigating androgen deprivation therapy (ADT) intensification in biochemically relapsed prostate cancer.

The phase 3 PRESTO study (NCT03009981) evaluated ADT alone vs ADT plus apalutamide (Erleada) vs ADT plus apalutamide, abiraterone acetate (Zytiga), and prednisone in men with biochemically recurrent prostate cancer and a prostate specific antigen (PSA) doubling time less than 9 months following radical prostatectomy.

Investigators evaluated intensified therapy on the backbone of ADT over a 52-week period in an effort to suppress PSA and enable longer treatment-free intervals, Aggarwal explains.

The top line interim analysis results for the primary end point of PSA progression-free survival (PFS) were presented at the 2022 ESMO Congress, Aggarwal continues. Patients treated in the 2 experimental arms featuring ADT plus apalutamide and ADT plus apalutamide, abiraterone, and prednisone experienced improved PSA PFS compared with patients who received ADT alone, Aggarwal concludes.

Rahul Aggarwal, MD, discusses the rationale for investigating androgen deprivation therapy intensification in biochemically relapsed prostate cancer.


Dr. Aggarwal on ADT Intensification in Biochemically Relapsed Prostate Cancer

Rahul Aggarwal, MD, an assistant professor of Hematology/Oncology, director of the STAND Clinic, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, discusses the future of androgen deprivation therapy (ADT) for patients with prostate cancer.

Studies have shown that early application of these potent therapies demonstrates benefit. There is a lot of ongoing drug development for high-risk patients who do not respond well to ADT or whose prostate-specific antigens do not decline fast enough after induction hormone therapy, says Aggarwal.

The impact of the early use of these therapies on the time to progression remains to be seen. The question also arises of how to treat more aggressive cancer for patients who are castration resistant, had their androgen receptor pathway suppressed, or have already been treated with abiraterone acetate (Zytiga), enzalutamide (Xtandi), or apalutamide.

Dr. Aggarwal on the Future of ADT for Patients With Prostate Cancer

Rahul Aggarwal, MD, assistant professor of Hematology/Oncology, Director of STAND Clinic, UCSF Helen Diller Comprehensive Cancer Center, discusses androgen deprivation therapy for patients with prostate cancer.

According to Aggarwal, we are moving away from a one-size-fits-all approach for androgen deprivation therapy to one that is adaptive for a patient’s specific disease state. Physicians are focused on the recent data in regards to abiraterone (Zytiga) and AR-targeted therapies.

Rahul Aggarwal, MD

Articles

Dr Aggarwal on the Activity of BXCL701 Plus Pembrolizumab in SCNC mCRPC

Dr. Aggarwal on Characteristics Associated With PSA PFS from the PRESTO Trial in Prostate Cancer

Dr. Aggarwal on ADT Intensification in Biochemically Relapsed Prostate Cancer

Dr. Aggarwal on the Future of ADT for Patients With Prostate Cancer

Dr. Aggarwal on Androgen Deprivation Therapy for Prostate Cancer