CE / CME
Physician Assistants/Physician Associates: 1.50 AAPA Category 1 CME credits
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: March 25, 2024
Expiration: March 24, 2025
BRCAAway: Phase II Study of Abiraterone vs Olaparib vs Abiraterone Plus Olaparib for mCRPC With HRR Mutations
Rana R. McKay, MD:
A number of interesting and potentially practice-changing studies in prostate, bladder, and kidney cancer were presented at ASCO GU this year. I will begin with the BRCAAway study. This is a randomized, open-label, multi-center, phase II trial in patients with mCRPC bearing germline and/or somatic mutations in BRCA1/2 or ATM.1
This very important study randomized 61 patients to receive either abiraterone/prednisone, olaparib, or the combination of both olaparib and abiraterone/prednisone. Crossover was allowed between the abiraterone and olaparib arms upon progression. The purpose of this trial was to understand how olaparib and abiraterone each contribute to therapeutic benefit. The primary endpoints for this study were PFS by RECIST and Prostate Cancer Working Group 3 criteria, as well as clinical assessment or death. Key secondary endpoints included ORR, PSA response rate, and safety.
BRCAAway: Baseline Characteristics
Rana R. McKay, MD:
Nineteen patients enrolled into the abiraterone arm, 21 in the olaparib arm, and 21 in the combination arm.1 The baseline demographics were approximately equivalent across the different arms of this trial in terms of baseline PSA, Eastern Cooperative Oncology Group (ECOG) performance status (PS) and sites of metastases. However, there was a slightly higher rate of BRCA2 mutations within the olaparib arm of the study.
In addition, it is important to note that patients were heavily pretreated with regimens that included docetaxel, darolutamide, enzalutamide, or sipuleucel-T. In the abiraterone group, 42% of patients received prior docetaxel compared with 19% each in the other arms.
BRCAAway: Efficacy Outcomes
Rana R. McKay, MD:
With regards to efficacy data, the study clearly demonstrated an improvement in PFS among patients who received the combination of abiraterone and olaparib, with a median PFS of 39 months, compared with 8.4 months for abiraterone and 14 months with olaparib.1
The ORR in the combination arm was also higher at 33%, vs either abiraterone or olaparib monotherapy, 22% and 14% respectively.
Finally, the PSA response rate was 95% with the combination of abiraterone and olaparib vs 61% and 67% with abiraterone or olaparib monotherapy, respectively. Clearly, there was greater efficacy with the combination of abiraterone and olaparib compared with either agent alone.
BRCAAway: Efficacy After Crossover Between Abiraterone/Prednisone and Olaparib Arms
Rana R. McKay, MD:
After disease progression, 8 patients in each of the abiraterone and olaparib arms crossed over to the other monotherapy treatment.1 The PFS, ORR, and PSA response rate data show that patients in both arms continued to respond to therapy after the crossover.
BRCAAway: Adverse Events in >15% of Patients
Rana R. McKay, MD:
With regard to AEs, more toxicity was observed with the combination of abiraterone and olaparib compared with either agent alone.1 The rate of grade 3 AEs was 19% with combination therapy, 14% with olaparib, and 21% with abiraterone. The rate of fatigue was markedly increased with the combination, with 71% of patients experiencing grade 1 to 3 fatigue vs 43% with olaparib and 16% with abiraterone. Anorexia was also higher for the combination. Rates of grade 1 to 3 and grade 3 anemia were the same for olaparib and the combination. Arthralgias and nausea were highest with olaparib monotherapy.
BRCAAway: Adverse Events in >15% of Patients Who Crossed Over Between Treatment Arms 1 and 2
Rana R. McKay, MD:
After the treatment crossover, the rate and type of toxicities associated with olaparib and abiraterone were as expected for patients who crossed over.1-3 Of note, there were no grade 3 AEs observed in patients who crossed over to the olaparib group, and no grade 4 or 5 AEs in either group.
BRCAAway: Clinical Implications
Rana R. McKay, MD:
I think the critical clinical implications of this study are that it demonstrates the activity of combination abiraterone with olaparib in comparison to either olaparib or abiraterone monotherapy. This study fills a gap that was not addressed in the phase III PROpel study.4 In PROpel, unselected patients were randomized to receive abiraterone with olaparib or abiraterone alone. However, that study did not have an olaparib monotherapy group to assess the individual contribution of olaparib in selected patients. Therefore, this study really demonstrates the role of olaparib alone in a population of patients with mutations in BRCA1/2 or ATM.
Terence Friedlander, MD:
I think BRCAAway is an interesting and timely study, particularly because the crossover component answers an important question about the sequence of therapies given for mCRPC in patients with HRR mutations. Until this study, healthcare professionals (HCPs) did not know whether to initiate treatment with an ARSI such as abiraterone or a PARP inhibitor like olaparib, if a patient had never received either. This study demonstrated that there are differences in tolerability between the 2 drugs.
I also think this study shows reasonably convincingly, despite small numbers, that giving patients the combination of an ARSI, along with a PARP inhibitor, makes more sense than monotherapy with either. Combination therapy seems to elicit longer durations of response.
I think it is a little hard to know how this is going to play out clinically, because ARSIs are strongly indicated in the hormone‑sensitive state for patients who have newly diagnosed metastatic prostate cancer in combination with ADT,5 although this study enrolled patients who had never received an ARSI and had progressed on ADT to the point of castration resistance. However, I think if I had a patient today who was receiving ADT alone, who had developed castration resistance and had a BRCA‑sensitizing mutation, I would strongly consider initiating both abiraterone and olaparib. I think it would be great to see future studies looking at giving PARP inhibitors earlier in the disease course, maybe at the time of hormone‑sensitive disease, to really better understand how this combination works.
CONTACT-02: Cabozantinib Plus Atezolizumab vs Second NHT for mCRPC After Progression on NHT
Rana R. McKay, MD:
The next study to highlight is the phase III CONTACT-02 study. I have eagerly been awaiting the results of this study since the press release in 2023 indicating that the data from this trial were positive. This is a multicenter, randomized, open-label, phase III trial of atezolizumab plus cabozantinib compared with a second novel hormone therapy (NHT) in patients with mCRPC that has progressed after initial NHT.6 Enzalutamide and abiraterone/prednisone were options for second NHT, which was required to be different than previous NHT. Progression was defined as either PSA or soft tissue progression and patients had to have measurable extrapelvic metastases.
The primary endpoints of the trial were PFS by RECIST v1.1 by blinded independent radiology committee (BIRC) in the PFS intention-to-treat population and OS in the ITT population.
CONTACT-02: Baseline Characteristics
Rana R. McKay, MD:
The baseline demographics between the 2 arms were well-balanced in terms of PS, age, region of enrollment, Gleason score at diagnosis, and sites of metastasis.6
Of importance, the disease state in which patients’ first NHT was received was also balanced between the 2 treatment arms with the majority receiving the first NHT for mCRPC. The median duration of the first NHT was approximately 1 year in both arms.
CONTACT-02: Progression-Free Survival
Rana R. McKay, MD:
With regard to the first primary endpoint, PFS, this was a positive study, meaning that treatment with cabozantinib plus atezolizumab resulted in a statistically significant improvement in PFS from 4.2 months with second NHT to 6.3 months with cabozantinib plus atezolizumab (HR: 0.65, 95% CI: 0.50-0.84, P = .0007).6 Similarly, the ITT population, not just the PFS ITT population, demonstrated a significantly greater PFS of 6.3 months with the combination therapy, vs 4.2 months with second NHT (HR: 0.64, 95% CI: 0.50-0.81, P = .0002).
CONTACT-02: Subgroup Analysis
Rana R. McKay, MD:
Considering PFS by subgroups, investigators observed a benefit from combination therapy across nearly all subgroups evaluated, with the exception of patients younger than 65 years of age.6 In particular, the cohort of patients that had liver metastases derived a remarkable benefit (HR: 0.43, 95% CI: 0.27-0.68). Patients who received prior docetaxel also experienced a notable benefit (HR: 0.57, 95% CI: 0.34-0.97).
CONTACT-02: Interim OS and Tumor Response
Rana R. McKay, MD:
In terms of OS, the data are still immature and interim in nature. The OS in the ITT population was 16.7 months with combination therapy vs 14.6 months with second NHT (HR: 0.79; 95% CI: 0.58-1.07).6 Although this analysis demonstrates a positive trend towards improved OS, these data are still immature and need to continue to evolve over time. The subgroup of patients who had liver metastases seemed to have an OS benefit with an HR of 0.60, (95% CI: 0.35-1.02) as well as those who had received prior docetaxel (HR: 0.56, 95% CI: 0.29-1.08).
Lastly, the interim response data demonstrate a 14% ORR for patients receiving the combination compared with 4% for patients in the control arm.
CONTACT-02: Additional Key Endpoints
Rana R. McKay, MD:
Additional key secondary endpoints included median time to chemotherapy, which favored the combination therapy.6
The median time to symptomatic skeletal events, median time to pain progression, and median time to deterioration of quality of life were similar between the 2 arms, as was PSA response.
CONTACT-02: Treatment Exposure and Discontinuation
Rana R. McKay, MD:
The median duration of exposure to the study treatment was 4.7 months for cabozantinib plus atezolizumab and 3.1 months for second NHT.6 In the combination arm, the median dose intensity for cabozantinib was maintained at 94%, while the median dose intensity for atezolizumab was slightly lower at 83%. Of note, the AEs leading to dose reduction in the cabozantinib plus atezolizumab arm were 40%, compared with 3% in the second NHT arm. However, the rate of treatment-related AEs that led to discontinuation of all treatment components was low overall, with 5% of patients in the combination arm and 2% in the second NHT arm halting treatment.
CONTACT-02: Adverse Events
Rana R. McKay, MD:
Overall, investigators reported increased grade 3/4 treatment-emergent AEs with the combination of cabozantinib plus atezolizumab, at 48% compared with 23% with second NHT.6 Looking specifically at the types of events that were common with cabozantinib and atezolizumab, the most common AEs were diarrhea, appetite decrease, fatigue, nausea, asthenia, AST and ALT elevation, anemia, weight decrease, hyperthyroidism, and hypertension. These are very classic side effects associated with cabozantinib.7
CONTACT-02: Clinical Implications
Rana McKay, MD:
I do not think these data support moving this regimen into the clinic at this time. I think the investigators did demonstrate a PFS benefit and that benefit was observed across subgroups, but the improvements were modest at best.
I think we need to see how the data evolve over time, including additional data regarding OS. This was a positive study, but the effect size was modest. Ultimately, we are going to have to wait and see what the final results show to assess treatment implications for our patients.
Terence Friedlander, MD:
Personally, I had a little bit of trouble interpreting this study and understanding the individual contribution of each drug. There was activity observed, but was that activity due to the cabozantinib, was it due to the atezolizumab, or was there some synergy between the two? I think that is hard to determine, especially in light of the fact that most PD-L1 checkpoint inhibitors have not been successful in clinical trials for prostate cancer. In fact, there are currently none approved for treatment of prostate cancer.8,9 In addition, cabozantinib has already been tested in multiple randomized phase III trials for mCRPC that failed to meet their primary endpoints, thus cabozantinib is not an approved therapy for mCPRC.10,11 Although I applaud the investigators for trying to develop a new, chemotherapy‑free regimen for this very advanced patient population, I am still unclear as to the activity of each drug in this regimen.
I think another drawback of this study is that the control arm was an NHT. A hormone therapy switch is a fairly weak therapy in prostate cancer. In fact, HCPs rarely see long‑term, durable responses with this type of treatment; less than half of patients will have any response either by PSA or radiographically.12,13 So, although the combination therapy is an improvement over the second NHT, it is hard to understand the magnitude of the therapeutic benefit from this comparison alone. In all, based on these data, even though this is a randomized, phase III study, I am not sure that this regimen is going to move forward. I would need to know more about the efficacy of this regimen before I recommend it for patients.
GETUG-18: Long-term Results of Radiation Therapy Dose Escalation With ADT for High-Risk, Localized Prostate Cancer
Terence Friedlander, MD:
GETUG‑18 was a randomized clinical trial assessing the 2 varying doses of radiation therapy for men with high‑risk, localized prostate cancer who are undergoing definitive radiation and hormone therapy.14 There has been a long history of trials demonstrating that the combination of ADT with radiation therapy is beneficial, especially in intermediate- and high‑risk localized prostate cancer.15 However, it was unknown whether a higher dose of radiation therapy combined with long-term ADT could provide additional therapeutic benefit, perhaps with less toxicity. GETUG-18 sought to compare high-dose radiation (80 Gy) and low-dose radiation (70 Gy), in the setting of long‑term hormone therapy.
This study enrolled patients who had high-risk, localized prostate cancer, defined as either PSA ≥20 ng/ml, Gleason score ≥8, or clinical stage T3 or T4 disease. Patients were randomized to either 70 Gy or 80 Gy dose of radiation therapy and 3 years of ADT.
The primary endpoint was PFS. Secondary endpoints included cancer‑specific survival, OS, and toxicity.
GETUG-18: Efficacy and Safety Outcomes
Terence Friedlander, MD:
At the 5-year mark, investigators observed a modest difference in PFS rates: 91.4% in the 80 Gy arm vs 88.1% in the 70 Gy arm.14 However, at 114.2 months median follow-up, the 10-year PFS rates diverge significantly, with 83.6% in the 80 Gy group vs 72.2% in the 70 Gy group—over an 11% absolute difference in PFS rate. With an HR of 0.56 (95% CI: 0.40-0.76) and P = .0005 this was a highly significant difference. These data clearly demonstrate that higher doses of radiation can affect PFS.
In terms of OS, there is a similar benefit to giving high‑dose radiation therapy compared with lower-dose radiation therapy. The high-dose group exhibited a 5-year OS rate of 93.4%, vs 88.7% in the low-dose group. The 10-year OS rate with 80 Gy was 77.0% vs 65.9% with 70 Gy; a more than 10% absolute difference. These data were highly significant in favor of the 80 Gy arm (HR: 0.61, 95% CI: 0.44-0.85, P = .0039).
The data also showed that toxicity was similar between the 2 doses. There was no difference in quality of life between the 2 groups.
GETUG-18: Clinical Implications
Terence Friedlander, MD:
I think this study addresses a number of questions about the correct dose of radiation therapy that should be given to high‑risk patients with localized prostate cancer. First, the data showed that a higher dose is beneficial in terms of long-term survival. I think one of the concerns HCPs had with using a higher dose was the possibility of longer term bowel or bladder toxicity. In GETUG-18, there was no significant long‑term toxicity from the higher dose of radiation. Altogether, the data support the use of higher dose radiation as a new standard of care for patients with high risk, localized disease.
However, this study does not really address the duration of ADT, nor does it address the contribution of the individual components of ADT. For example, these data do not speak to whether HCPs should use a luteinizing hormone-releasing hormone agonist alone or in combination with an ARSI. I think upcoming studies should further investigate the value of adding ARSIs to see how HCPs can improve outcomes for these patients even more.
Rana R. McKay, MD:
GETUG-18 was a very important study for patients with high-risk prostate cancer who were receiving long-term ADT with radiation. I think these data really highlight the need for more modern day, higher intensity, local radiation for patients with high-risk localized disease who are receiving radiation and long-term ADT.
HPN328: Phase I/II Trial of a DLL3-Targeting T-Cell Engager in Neuroendocrine Prostate Cancer
Terence Friedlander, MD:
DLL3 is expressed on most neuroendocrine tumors, including neuroendocrine prostate cancer and thus is a molecular target.16 It is upregulated in advanced disease and does not seem to be widely expressed by healthy tissues. HPN328 is a DLL3-targeting T‑cell engager that elicited dramatic reductions in tumor size and tumor growth in preclinical models.17
This open-label phase I/II study is investigating HPN328 in men with advanced neuroendocrine prostate cancer or small cell lung cancer with relapsed or refractory disease, or any high‑grade neuroendocrine tumors for which a standard of care therapy is not available.18 The study is a 3+3 dose escalation study which has enrolled 85 patients. HPN328 was administered at a 1 mg priming dose (n = 61) then in the following cohorts: 6 mg weekly, 12 mg weekly or biweekly, or 24 mg weekly or biweekly.
Of 85 patients, 21 had urologic neuroendocrine carcinomas and 15 of those patients had neuroendocrine prostate cancer. The majority of the patients enrolled (n = 53) had small cell lung cancer and 11 had other neuroendocrine tumors. The baseline characteristics of the subset of patients with genitourinary cancers were not substantially different than the total population in terms of prior therapies (median = 3). However, a lower proportion of patients in the genitourinary subgroup had brain metastases (9.5% vs 41.2%), and a higher proportion had liver metastases compared with the total patient population (61.9% and 51.8%, respectively).
HPN328: Safety in the Total Study Population
Terence Friedlander, MD:
In terms of AEs in this study, there were some dose-limiting toxicities (DLTs) at the priming dose of 2 mg and the priming dose was lowered to 1 mg.18 However, there were no DLTs observed at target doses and the maximum tolerated dose was not reached.
Among the study population, the HPN328 was fairly well tolerated, with grade ≥3 treatment-related AEs occurring in 24.7% of participants. Of note, any grade cytokine release syndrome (CRS) occurred in almost 60% of patients and grade ≥3 in 3.5%. Fortunately, once CRS occurred, it rarely occurred at a level higher than grade 1 after the first event. Altogether, this rate of CRS was not surprising since HPN328 is a T‑cell engager that binds both CD3 and DLL3; some activation of T‑cells with this drug is expected.19 Dysgeusia and fatigue were also fairly common, but not unexpected.
HPN328: Antitumor Activity
Terence Friedlander, MD:
The data show that this drug is fairly active. Among evaluable patients of all tumor types (n = 50), the majority had some tumor shrinkage, with an ORR of 56%.18 The confirmed response rate was lower at 31%, but even this rate is notable, considering this is a phase I trial. The disease control rate was also fairly high at almost 70%.
Specifically in patients with genitourinary neuroendocrine cancers, including neuroendocrine prostate cancer, the confirmed response rate was 25%, with an ORR of 58%. In this group of patients, the disease control rate was 83%. Some patients with genitourinary cancers other than prostate cancer experienced impressive tumor shrinkage, including 1 complete response.
These data imply that HPN328 is not solely geared towards neuroendocrine prostate cancer but may be effective for any DLL3 expressing tumor.
HPN328: Clinical Implications
Terence Friedlander, MD:
I think this study is quite exciting for a number of reasons. From the start, it is notable because as a phase I trial, it is the first look at the activity of HPN328 in neuroendocrine carcinomas that express DLL3. I also think this is interesting data where we see fairly broad activity across a variety of neuroendocrine carcinomas with DLL3 expression, though these data need to be reproduced in larger patient cohorts and in a randomized trial before it can be used in patients. I would also like to see longer-term toxicity data to determine if there are any potential longer-term problems with this therapy.
I think an important question to address going forward is patient selection for this therapy. Some of the data that I did not discuss in detail demonstrated that there were mixed responses in some patients, where select lesions progressed and others responded to therapy.18 Based on DLL3 staining, the lesions that progressed had lower DLL3 expression, indicating that escape from this drug could be mediated by lower expression of DLL3. I think as this drug develops further, it would be helpful to have companion diagnostics to understand the level of DLL3 expression needed for a likely response and whether homogeneous DLL3 expression across tumors is required for efficacy. The variable response also calls attention to the possibility of incorporating this drug into combination therapy, perhaps with a checkpoint inhibitor or other agents that target DLL3‑negative disease.
All in all, this is a patient group with very few effective treatment options. I greatly look forward to additional trial results with this agent as it could potentially be very impactful in the treatment of neuroendocrine carcinomas.
Rana R. McKay, MD:
I think what was really remarkable to see from this trial was that there were dramatic responses observed across all tumor types. Specifically in patients with genitourinary neuroendocrine tumors, investigators observed striking activity for a patient population and tumor type that have historically been very resistant to treatment. I am very excited about the prospect of DLL3-targeting therapies, including bispecific antibodies, antibody–drug conjugates (ADCs), and other targeted therapies for patients that have neuroendocrine differentiation or neuroendocrine tumors as this is a true unmet need in the clinic.
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