Balic: PALOMA-2 OS data presented at ASCO lacked to demonstrate OS benefit in favor of palbociclib. Dr. Finn has implied that partly this was due to a significant proportion of patients who were lost to follow-up and the patient population. How do you interpret these data and will there be an impact on the use of palbociclib in metastatic setting in the future?
Wimmer: The long-awaited results regarding OS showed only a numerical benefit that did not reach level of significance. One third of the patients had missing data regarding overall survival due to lost to follow-up or withdrawal of consent, which limited the assessment of the OS.
Nevertheless, it can be excepted that all possible subgroups had been investigated in the hope of detecting OS differences between patients in the treatment and the control arm. Even in a subgroup analysis including patients with longer follow-ups, they only observed a trend of improved OS. As a side note: the PALOMA-2 trial met its primary endpoint of significantly improved PFS; nevertheless, a significant OS benefit could not be presented at the ASCO 2022.
Suppan: There might be several reasons for the lack of statistical significance, but in the end these results cannot be ignored. In my opinion there will still be patients with metastatic breast cancer in the future qualifying for a treatment with palbociclib, especially older patients. Considering the data from the MAINTAIN trial when patients received ribociclib with a new endocrine therapy partner after progression under CDK4/6 inhibition and endocrine therapy, all of our patients should be offered ribociclib once during their treatment.
Silovski: The PALOMA-2 study investigated addition of palbociclib to aromatase inhibitor in the first-line treatment of hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (mBC) and initially confirmed efficacy of palbociclib, reached its primary endpoint, and almost doubled progression-free survival (PFS) by addition of palbociclib to mono endocrine therapy (ET) − aromatase inhibitor (AI) versus ET alone (24.8 versus 14.5 months). Although CDK4/6 inhibitors as class improved overall survival (OS) of HR+/HER2− metastatic breast cancer patients, in the PALOMA-2 study, after 7.5 years of follow-up and required number of survival events, results did not reach key secondary endpoint − OS improvement, with addition of palbociclib to AI (53.9 versus 51.2 months). When we closely look at OS data, there could be few reasons for this finding. One of the reasons could be significant dropout from the study, as even one third of patients were missing survival data − 13% of patients in the palbociclib arm and 21% in the placebo arm, due to consent withdrawal or lost to follow-up. The OS analysis was adjusted by exclusion of the patients missing survival data, which most certainly has provoked some bias. Further on, the PALOMA-2 study has included quite diverse patient population, as 20% of the patients had disease-free interval (DFI) less than 12 months from finishing early breast cancer treatment. When the OS was analyzed solely in the subgroup of patients with DFI longer than 12 months, OS in the palbociclib group was 64 months compared to 44.6 months in the placebo group, which is comparable to the OS data from the MONALEESA-2 study, which confirmed significant OS prolongation by addition of CDK4/6 inhibitor ribociclib to the aromatase inhibitor. Still, PALOMA-2 OS data of over 50 months in the allcomers and over 60 months in clearly endocrine-sensitive patients, positions palbociclib as full-fledged CDK4/6 inhibitor in the first-line treatment of endocrine-sensitive postmenopausal population, especially due its favorable toxicity profile, which makes it the optimal choice in old and fragile patients with lots of comorbidities.
Brunner: The OS data from the PALOMA-2 study were eagerly awaited at ASCO, especially as the era of CDK4/6 inhibitors began 7 years ago at ASCO with the presentation of the primary endpoint, PFS of the PALOMA-2 study (PFS 24.8 months). Both the data from the MONALEESA-2 study (25.3 months) and the data from the MONARCH 3 study (28.8 months) confirmed the clear advantage in PFS with the addition of CDK4/6 inhibitors in HR-positive breast cancer in the metastatic setting. Therefore, this therapy is now the standard of care in metastatic HR-positive HER2-negative breast cancer.
Positive OS data are already available for the MONALEESA-2 in postmenopausal women, as well as the MONALEESA-7 in premenopausal women and the MONALEESA-3 in combination with fulvestrant. In the second-line setting MONARCH 2 also reported positive OS data, while MONARCH 3 results on OS are still pending.
When Finn et al. presented the OS data, a numerically increased OS in favor of palbociclib became apparent, but the results were not significant (HR = 0.96; p = 0.43). Furthermore, the absolute delta in survival was much less compared to the MONALEESA trials. One way Finn tried to explain this in his presentation is by showing that there was a substantial amount of data missing in the follow-up and that the loss was unbalanced between the two arms. This imbalance must be taken into consideration when evaluating the study as it might make the interpretation of the results more difficult. Another explanation for the discrepant result compared to the OS data of the MONALEESA-2 study could also be the patient characteristics. The proportion of early relapse patients (DFS ≤12 months) was significantly higher than in MONALEESA-2, presenting patients with carcinomas that are endocrine resistant with a assumed worse prognosis, thus probably having an impact on the trial results. In an unplanned subgroup analysis that took into account the PALOMA-1 and PALOMA-2 data with patients with DFS ≥12 months, it was then possible to show a longer survival in favor of palbociclib. Looking at these results and also the results in the adjuvant setting allows us to come to the conclusion that there might be more differences between the individual CDK4/6 inhibitors than we expected. We see this both in the different structure and in the side effect profile. However, it must also be noted that this is the study of CDK4/6 inhibitors with the longest follow-up (7.5 years) and that 10% of all patients in this study are still receiving therapy with palbociclib.
Two essential questions now arise for clinical practice: (1) How should we deal with the patients who are currently on palbociclib? (2) Which of the 3 available CDK4/6 inhibitors should be offered to new patients?
To answer the first question: There is currently no data that indicates patients on palbociclib should be switched to another CDK inhibitor. If the patient tolerates the drug well, she should continued treatment (never change a winning team).
Concerning the second question: The already positive OS data on ribociclib and the OS data from the PALOMA-2 data now presented at ASCO must be taken into account in everyday clinical practice.
Ribociclib resulted in the strongest OS data available so far, which is a fact that cannot be neglected. However, the patients' compliance and comorbidities as well as the side effect profile play an important role in the choice of medication. Additionally we have seen hints that if the patient has an endocrine-sensitive disease (DFS ≥12 months), palbociclib achieved comparable results and is therefore still considered a good choice for these patients. Regarding abemaciclib, we eagerly await the presentation of the OS data from the MONARCH 3 study.
Balic: ADCs are changing the treatment landscape of metastatic breast cancer patients. So far, we have had approval of Her2-directed ADCs in Her2-positive breast cancer and Anti Trop II ADC sacituzumab govitecan in triple-negative breast cancer. TROPiCS-02 and DESTINY-04 have been presented at ASCO. Where do you see overlap between these 2 studies, and how will they be implemented in the treatment of metastatic breast cancer patients?
Wimmer: First, HER2-low, which is defined by 1+ or 2+ in IHC without gene amplification, is a very interesting new category. This lower level of Her2 expression − as Shanu Modi, MD from the Memorial Sloan Kettering Cancer Center explained at ASCO 2022 − was formerly put under the umbrella of Her2-negative BC. Therefore, if in combination with hormone receptor negativity, these patients were treated as TNBC patients. As DESTINY-04 could confirm, significant improvement of survival could be achieved even in metastatic HR− Her2-low patients, who would have been formerly treated as TNBC. In HR+ Her2-low patients, the addition of trastuzumab deruxtecan (T-DXd) led to a doubled progression-free survival when compared to chemotherapy alone. In the TROPiCS-02 trial, the addition of sacituzumab govitecan − an anti-Trop2 antibody drug conjugate − to standard chemotherapy in HR+, Her2− metastatic breast cancer patients was investigated. When compared to chemotherapy alone, sacituzumab govitecan led to a moderate benefit of 1.5 months in progression-free survival (5.5 versus 4.0 months). In 2020, this agent already showed improvement in the therapy of TNBC; however, in the HR+ Her2− patient population, only small survival benefits were observable. It has to be considered that heavily pretreated patients were included in this trial. The overlap of the TROPiC-02 and the DESTINY-04 trial is that both demonstrated benefits of next-generation antibody drug conjugates (ADC) for new breast cancer “subtypes” (Her2 low, TROP-2 overexpression) aiming to offer patients with therapy refractory metastatic breast cancer a new therapeutic option. Both trials addressed a difficult-to-treat population, which was already treated with up to 4 lines of chemotherapy (up to 2 lines in DESTINY-04) and CDK4/6 inhibitors and which had an endocrine therapy refractory disease.
Suppan: Both studies provide us with a new treatment option for patients with metastatic luminal breast cancer. DB04 showed impressive data for this patient population and therefore T-DXd will be implemented in the treatment algorithm for metastatic Her2-low breast cancer. TROPiCS-02 included more heavily pretreated patients and still showed a significant benefit of sacituzumab govitecan compared to treatment of physician's choice in later line. As we already know, ADCs after progression on ADCs do work, both drugs are very important for these patients considering their potential side effects.
Silovski: ADC seems to be a novel and exciting therapy approach in metastatic breast cancer which enables, due to antibody carrier, targeted delivery of very powerful cytotoxic drugs, directly to the tumor with reduced potential of serious side effects.
Both studies, TROPiCS-02 and DESTINY-04, were presented at ASCO 2022. They investigated the role of third-generation antibody drug conjugates (ADC) sacituzumab govitecan and trastuzumab deruxtecan in patients with metastatic breast cancer who were significantly pretreated.
About 50% of metastatic breast cancer patients are classified as HER2 low and the DESTINY-04 study included exactly this specific patient population. HER2-low-positive breast cancer was determined by immunohistochemistry (IHC) staining 1+ or 2+ and in situ hybridization negativity (ISH–). The DESTINY-04 study included patients with HR-positive (89% of patients) as well as HR-negative tumors who were priorly treated with a median of three lines of systemic therapy and a median of two prior lines of endocrine therapy, whereas roughly 70% received prior CDK4/6 inhibitor. All patients who had HR-positive disease were endocrine resistant. Trastuzumab deruxtecan in comparison to the therapy of physician's choice, significantly improved progression-free survival (PFS) and overall survival (OS) for 4.8 and 6.6 months, respectively, in the overall study population. The results were similar in the HR-positive population, with an improvement of 4.7 months in PFS and 6.4 months in OS. Therefore, trastuzumab deruxtecan presents a new standard of care for the HER2-low population.
On the other hand, the TROPiCS-02 study included patients with the most common subtype of metastatic HR-positive, HER2-negative breast cancer with no specific immunohistochemistry determination of HER2 expression who were priorly heavily pretreated with a median of three prior lines of chemotherapy, and prior therapy with taxanes, CDK4/6 inhibitors, and endocrine therapy in any setting. Almost all patients (95%) had visceral disease. The results of this study were not even close to those of DESTINY-04 as the improvement of PFS was only 1.5 months with sacituzumab govitecan in comparison to the treatment of physician's choice. This clinically modest PFS improvement can be partially explained by the study population which was “worse” comparing to the DESTINY-04 study population, according to its characteristics − very difficult to treat and extremely pretreated. Though, despite early dropout within the first 2 months of therapy, patients who responded had durable response, with PFS curves which continued to be separated over the follow-up period. After 12 months, 21% of patients treated with sacituzumab govitecan versus 7% of patients treated with therapy of physician's choice response were alive and did not experience progression.
We can conclude that patients with HR-positive, HER2-low-positive disease who are endocrine resistant and heavily pretreated were included in both studies. Results of DESTINY-04 significantly overcome those of TROPiCS-02. Therefore, in this subgroup of patients, priority in treatment should be given to trastuzumab deruxtecan in comparison to sacituzumab govitecan. Further on, it would be interesting to see subgroup analysis and results of sacituzumab govitecan after longer follow-up to recognize some subgroup of patients where therapy with sacituzumab govitecan could precede treatment with trastuzumab deruxtecan, as it is very well known that in further lines of therapy, shorter duration of benefit is excepted.
Brunner: Two studies were presented at ASCO, where the effects of both SG and T-DXd in patients with metastatic HR-positive breast cancer were examined. In both trials the ADCs were compared to TPC chemotherapy. A direct comparison of these studies is difficult due to differences in the patient characteristics. Patients in the TROPiCS-02 study had a median of 3 prior chemotherapy regimens, while a median of one chemotherapy regimen was reported for HR+ patients in the DESTINY-Breast04 study. Regarding prior endocrine therapy, all patients in TROPiCS-02 had to be pretreated with at least 1 CDK4/6, while pretreatment with CDK4/6 was optional, and 70% of patients in DESTINY-Breast04. There was an overlap in both studies regarding HER2 status. Patients with HER2+ or HER2++ and a negative SISH score could be included in both the DESTINY-Breast04 and the TROPiCS-02. TROPiCS-02 also included HER2 0 carcinomas. A significant PFS benefit could be shown in both studies, but in the TROPiCS-02 study the difference was 1.5 months. While the heavily pretreated population has to be taken into account, the clinical relevance of a prolonging PFS by 1.5 months in relation to the side effects must certainly be discussed. Due to the undisputedly outstanding PFS data in DB04, T-Dxd will find its way into everyday clinical practice in the therapy of hormone receptor-positive Her2-low metastatic breast cancer. Looking at the group of patients in the TROPiCS-02 study, a total of 35% of the patients were HR positive and HER2 0 (negative). SG could possibly be a therapy option for these patients. In both studies there was no new histopathological confirmation of the metastases, so it is quite possible that certain tumors in the TROPiCS-02 study were already behaving like TNBC. A histological confirmation of the metastases in tumor progression before applying a targeted therapy should be considered. The main indication for SG for the time being will be in metastatic TNBC after 2 previous lines of chemotherapy, with the best evidence for ADC in this setting so far. DB04 also showed positive results in HR–/HER2-low patients, but sample size in this population was small (n = 58). But in addition to the indication as therapy of metastatic HER2-positive breast cancer in second-line therapy, T-Dxd will now also be an additional therapy option for metastatic HER2-low carcinoma. Ongoing studies will show whether the ADCs can also be used in earlier lines of therapy. And sequential use of ADCs will become a part of future oncology practice.
Balic: What are the challenges of the overwhelmingly positive results of the DESTINY-04 clinical trial for the clinical implementation?
Wimmer: On the one hand, this trial might redefine the classification of BC, so that a reliable and consistent IHC will be mandatory for the identification of Her2-low patients. On the other hand, as we already could observe in the DESTINY-04 trial, we have to deal with new toxicities. This unique lung toxicity − interstitial pneumonitis − was found in 12.1% in the T-DXd arm versus in 0.1% in the chemotherapy arm, respectively. This safety concern has to be monitored closely and the selection of suitable patients as well as the knowledge of the management of this specific interstitial lung disease will be crucial for the clinical practice.
Suppan: Her2 scoring by our pathologists has gained much more importance since there is data on Her2-low breast cancer. Moreover side effects of T-DXd such as ILD and high drug costs can be challenging for the daily routine.
Silovski: Very challenging would be defining the optimal position of trastuzumab deruxtecan in the treatment sequence in HER2-low-positive HR-positive as well as HR-negative (currently triple negative) metastatic breast cancer. To define optimal trastuzumab deruxtecan position, the recognition of resistance mechanisms is very important. It is to discover whether most important is the loss of HER2 expression or mutation changing HER2 receptor conformation or, on the other hand, resistance to cytostatic payload topoisomerase I inhibitor or eventually some other intra- or extracellular mechanisms. Further on, defining HER-low tumor status is also a challenging point as immunohistochemistry is a subjective method and more objective methods for defining HER2-low status are required. Finally, for the full clinical implementation of trastuzumab deruxtecan in the treatment of HER2-low-positive tumors, will be overcoming financial toxicity.
Brunner: The outstanding positive results are certainly practice-changing for everyday clinical practice and T-Dxd should no longer be withheld from patients with metastatic HER2-low breast cancer. In the past, the indication for targeted anti-HER2 therapy was the Her2 positivity of the tumor, which was defined as Her2++ and SISH/FISH positive or HER2+++. Her2++ SISH/FISH negative as well as Her2+ were considered not eligible for HER2 targeted therapy. As a result, the nomenclature of carcinomas regarding HER2 status was limited to HER2 positive or negative. With the presentation of the DESTINY-04 data, it will now again be necessary to specify the immunohistochemical score more precisely. Another challenge will sure enough be the management of side effects. As already presented in DESTINY-Breast01 and DESTINY-Breast03, the ILD plays an important role that can even lead to death. At the presentation of the DESTINY-Breast04, 3 cases of grade 5 ILD occurred. Managing this side effect well will be of the utmost importance in everyday clinical practice. If ILD occurs, adequate imaging by means of a CT scan must be carried out at an early stage, the therapy must be paused and an immediate start with corticosteroids is essential. In the case of higher-grade ILDs, the therapy must be stopped. Due to the heterogeneity of the tumor, the IHC should not be determined in the case of tumor progression on the primary tumor at the time of initial diagnosis. Before switching to a targeted therapy, a recent biopsy of a progressive metastasis should be used to ensure that the target is still being expressed on the tumor. The presentation of the study also showed that not only patients HR positive and HER2-low benefit from therapy with T-Dxd, but also patients with HR-negative Mamma Ca. It was only a small collective of 60 patients, surely more studies are needed here.
Balic: In the early-stage breast cancer, pembrolizumab has been approved for neoadjuvant and adjuvant treatment of triple negative breast cancer. Update with RCB score analyses was presented at the ASCO annual meeting! Is there any particular group with especially great benefit of pembrolizumab? Can we determine whether there are patients where the adjuvant phase can be omitted?
Wimmer: The KEYNOTE-522 trial surely paved the way for the combination of immunotherapy with chemotherapy in early TNBC. The addition of anti-PD-1 pembrolizumab to anthracycline/taxane-based neoadjuvant chemotherapy, followed by adjuvant pembrolizumab, showed significant increased pathologic complete response rates and event-free survival. Although earlier analyses (in NEJM, 2020) suggested greater benefit of neoadjuvant anti-PD-1 treatment in nodal-positive disease, recent sensitivity analyses of the KEYNOTE-522 trial confirmed beneficial effects of adding pembrolizumab in all subgroups, independently of nodal stage, disease stage, or other factors as PD-L1 status. As presented, patients with residual disease after neoadjuvant pembrolizumab have to face worse prognosis. However, the benefit of adjuvant pembrolizumab in patients that achieved pCR has to be further investigated.
To conclude, further research is needed to identify which patients will benefit most from the combination of chemotherapy with immunotherapy. Additionally, the optimal sequence and if immunotherapy can be omitted in the adjuvant setting when pCR was achieved under neoadjuvant pembrolizumab needs to be evaluated.
Suppan: The greatest benefit of added pembrolizumab to neoadjuvant chemotherapy was seen in the RCB-2 group. Patients responding with RCB-0/1 to neoadjuvant therapy might be candidates for omitting adjuvant pembrolizumab in the future. However, studies answering this question are already planned and therefore we should wait for these results. In addition the study showed that the majority of immune-related side effects occurred in the neoadjuvant phase.
Silovski: It is well known that attainment of pathologic complete response is a marker of better outcome. PD-L1 expression in the tumor is a predictor of good therapeutic response to chemotherapy, even without addition of checkpoint inhibitors. Benefit gained from immunotherapy in early breast cancer is not dependent of PD-L1 expression, but PD-L1-positive tumors are more likely to respond to the immunotherapy.
Primary results of KEYNOTE-522 study have already shown statistically and clinically significant improvement in obtaining pCR and prolonging EFS with addition of pembrolizumab to neoadjuvant chemotherapy (combination of paclitaxel and carboplatin for four cycles followed by combination of epirubicin and cyclophosphamide) and continuing with additional 9 cycles of adjuvant pembrolizumab.
Node-positive tumors benefit most from addition of pembrolizumab, but pembrolizumab addition to the chemotherapy prolonged event-free survival irrespectively of nodal status.
The rate of complete pathologic response was much higher in patients with stage 2 and 3 breast cancer. Even without a pathologic complete response, the addition of pembrolizumab to the chemotherapy improved 3-year event-free survival possibly due to the downward shift in residual cancer burden.
At the ASCO 2022 association between RCB categories and EFS was assessed. Increased RCB score was associated with worse EFS. Results showed that addition of pembrolizumab lowered RCB values in patients with residual disease and prolonged EFS in all RCB categories even in RCB-3 category although interpretation of these results was limited due to small sample size. The most pronounced beneficial effect from addition of pembrolizumab was observed in patients with moderate residual disease RCB II category. After addition of pembrolizumab to the neoadjuvant chemotherapy, the proportion of patients with large amount of residual, RCB III category has lessened significantly and counted 6–8% of all triple-negative tumors treated with neoadjuvant therapy.
According to the presented results, addition of pembrolizumab to the neoadjuvant chemotherapy is justified for all but the smallest triple-negative breast tumors.
KEYNOTE-522 showed 10% improvement in 3-year EFS in patients not achieving pCR whereas only 2% improvement was observed in those patients achieving pCR.
Those results, together with results of GeparNuevo study (which also showed survival benefit with addition of immunotherapy to the standard neoadjuvant chemotherapy), indicate similar survival outcomes whether immunotherapy is administered only in the neoadjuvant or in the neoadjuvant and in the adjuvant setting, which could potentially support strategy of adjuvant immunotherapy de-escalation in patients achieving pCT with neoadjuvant chemoimmunotherapy treatment. Though, at this point, as no prospective study results exist, standard treatment should include adjuvant pembrolizumab administration.
In patients with residual disease there are also data from other clinical trials which support adjuvant therapy with capecitabine or olaparib in patients with germline BRCA mutations but there is currently no data which would support combination of those agents with pembrolizumab so these combinations are to be investigated.
Pembrolizumab added to neoadjuvant chemotherapy improves survival in patients with early triple-negative breast cancer and disclose subset of patients who will not do well and in whom investigation of optimal additional therapies is needed.
Brunner: KEYNOTE-522, a prospective randomized study on the treatment of Stage II-III TNBC in the neoadjuvant setting, showed the clear advantage in terms of both pCR and EFS in favor of pembrolizumab in combination with chemotherapy versus chemotherapy alone. This led to the approval of the immune checkpoint inhibitor in TNBC in the neoadjuvant setting in combination with chemotherapy and in the adjuvant setting as a single agent for high-risk TNBC.
An exploratory analysis was now carried out again at ASCO as part of KEYNOTE-522 and the connection between the RCB score (residual cancer burden score 0, 1–3) and EFS was analyzed in more detail. RCB 0 = pCR; RCB 1 = minimal burden; RCB 2 = moderate burden; RCB 3 = extensive burden. Patients with complete remission (RCB score 0) showed an EFS of almost 93% after 36 months in both groups, with the difference between both groups with or without pembrolizumab being minimal (7% in favor of pembrolizumab). The same result with very good EFS data (84% after 36 months) was also seen in the group of patients with RCB 1. The patients with RCB 2 had the greatest benefit from therapy with pembrolizumab. These patients also made up the largest part of the patient collective. In RCB 3, there was a small numerical benefit for pembrolizumab.
Consequently, it remains to be debated whether patients who achieved a pCR with pembrolizumab should continue to be offered the adjuvant pembrolizumab, especially since both the group of patients with chemotherapy and the addition of pembrolizumab had an excellent EFS of >93% after 36 months. Pembrolizumab therapy also needs to be discussed in patients with RCB 3. These patients have a very high probability of recurrence and it will be of particular importance to offer postneoadjuvant therapy (pembrolizumab KEYNOTE-522, capecitabine CREATE-X, olaparib OlympiA, or inclusion in trials like SASCIA). And yet another strong argument for routine use of RCB score in everyday clinical practice to decide on therapy and offering postneoadjuvant therapy to patients with RCB 2 and 3.
Balic: Does the presentation of the final ABCSG 18 results have the potential to impact the clinical use of bone supportive agents in early-stage breast cancer?
Wimmer: I think the evidence for the addition of adjuvant denosumab during aromatase inhibitor therapy is clear. An injection applied twice a year that not only decreases fracture rates significantly but is also associated with beneficial disease-free, bone metastasis-free as well as overall survival has to be considered as standard supportive therapy in postmenopausal women suffering from HR+ breast cancer.
Suppan: Despite the fact that bone health was not a study endpoint, the results of ABCSG 18 are great. Denosumab 60 mg given every 6 months should be considered as a treatment option for the use in adjuvant setting as an alternative to bisphosphonates and should also be implemented in the guidelines.
Silovski: The ABSCG 18 study was investigating addition of denosumab to adjuvant endocrine therapy with aromatase inhibitor compared to addition of placebo in almost 3,500 patients. The results of the ABSCG 18 study were presented on ASCO 2022 after 8 years follow-up. DFS was improved by addition of denosumab resulting by an absolute 9-year DFS difference of 3.5% (79.4% versus 72.9%). Addition of denosumab improved bone metastases-free survival (BMFS) by 19% and overall survival (OS) by 20%. Further on, previously reported marked reduction in clinical fractures persisted − with denosumab, there were significantly fewer fractures, 24% less than in placebo group. Adjuvant denosumab was given 60 mg s.c. every 6 months during the aromatase inhibitor therapy and is considered safe. Although this study had clearly positive results, it is completely different to the D-CARE study which was conducted in 4,500 patients and which had, on the other hand, negative results. This difference is probably due to the different study design − D-CARE was specifically looking at denosumab impact on disease-related outcomes but not on bone-related outcomes and found no effect. In this study denosumab was given in the dose of 120 mg s.c. every 3–4 months for 6 months and afterwards every 12 weeks up to 5 years. So, the dosing schedule was different in those two studies with an accent to the fact that denosumab schedule was more favorable in ABSCG 18 and not connected to serious side effects as denosumab was given every 6 months.
In comparison to the ABSCG 18 study, which included patients with HR-positive disease treated with adjuvant endocrine therapy, D-CARE included postmenopausal patients with all breast cancer subtypes. I believe that the difference in study population as well as dose and schedule of denosumab application mostly had driven the study results. The biggest positive influence is expected in postmenopausal patients with HR-positive early breast cancer treated by aromatase inhibitors. The ABSCG 18 study findings mirror the results from clinical trials with bisphosphonates which have found bone- and disease-related improvements with addition of bisphosphonates which are currently the guideline-recommended standard of care for bone-strengthening adjuvant treatment among early-stage breast cancer.
Therefore, according to the results of the ABSCG 18 study, we can conclude that addition of denosumab to aromatase inhibitors as adjuvant endocrine therapy in patients with HR-positive early breast cancer could represent a therapeutic option besides bisphosphonate (zolendronic acid, oral ibradronate, or clodronate) in this subgroup of patients.
Brunner: ABCSG 18, a prospective, randomized multicenter study, examined the value of denosumab 60 mg every 6 months for a total of 3 years in over 3,000 hormone receptor positive postmenopausal patients. The influence of denosumab therapy on newly occurring bone fractures as well as on DFS and OS was examined. During his presentation, Gnant presented impressive data on the reduction of bone fractures. It should also be mentioned that this benefit comes with very few side effects overall under the therapy. The dreaded atypical femoral fractures could only be observed in one patient and the observed MRONJ under denosumab could only be diagnosed in one patient. Additionally adjuvant administration of denosumab also improved DFS and overall survival. Due to the very large-scale study with a very long follow-up and extremely good data regarding the reduction of bone fractures and improvement of survival endpoints, the therapy should be offered to HR-positive postmenopausal patients with a high risk of recurrence. In the risk-benefit analysis, it is clearly in favor of denosumab, especially since there were hardly any side effects with this therapy. If you take into account the costs that are caused by osteoporosis each year, this therapy is also cost-effective.
Chair
Dr. Marija Balic
Departement of Internal Medicine
Division of Oncology
Medical University Graz
Auenbruggerplatz 15
8036 Graz, Austria
E-Mail marija.balic@medunigraz.at
Participants
Dr. Christine Brunner
Department of Obstetrics and Gynecology
Medical University of Innsbruck
Anichstrasse 35
6020 Innsbruck, Austria
E-Mail c.brunner@tirol-kliniken.at
Dr. Tajana Silovski
Department of Oncology
UHC Zagreb
Kispaticeva 12
10 000 Zagreb, Croatia
E-Mail tsilovski@gmail.com
Dr. Christoph Suppan
Department of Internal Medicine
Clinical Division of Oncology
Medical University of Graz
Auenbruggerplatz 15
8036 Graz, Austria
E-Mail christoph.suppan@medunigraz.at
Dr. Kerstin Wimmer
Department of Surgery
Division of General Surgery
Medical University of Vienna
Waehringer Guertel 18–20
1090 Vienna, Austria
E-Mail kerstin.wimmer@meduniwien.ac.at