Adjuvant Bisphosphonates: Winner in Postmenopausal Breast Cancer
Adjuvant bisphosphonates reduce the risk of bone metastases by about one-third and improve breast cancer–related survival by 17% in postmenopausal women with early breast cancer, according to a large meta-analysis reported here. Bisphosphonates had no effect on premenopausal women in the adjuvant setting.
“Adjuvant bisphosphonates had no significant effect on distant recurrences outside the bone, but the risk reductions in bone recurrence and breast cancer death were similar regardless of estrogen receptor status, node status, and use/nonuse of chemotherapy,” stated Robert E. Coleman, MD, University of Sheffield, UK, who presented the meta-analysis results on behalf of the Early Breast Cancer Trialists’ Collaborative Group. He emphasized that results were similar with clodronate and the aminobisphosphonates (65% of patients taking bisphosphonates were taking zoledronic acid).
Bisphosphonates are thought to work by embedding in bone and interrupting the vicious cycle leading to bone breakdown, Coleman told listeners.
The meta-analysis was based on 36 randomized trials comparing adjuvant bisphosphonates with placebo or no bisphosphonate conducted over the past 15 years. Seven of the trials were of oral clodronate and 29 of zoledronic acid.
The meta-analysis was based on individual patient data for 22,982 patients (17,791 of all patients received clodronate or an aminobisphosphonate); a total of 11,036 women were postmenopausal.
With 10 years of follow-up, in the overall analysis, adjuvant bisphosphonates had no significant effect on all recurrences (26.5% with no bisphosphonate, 25.4% with bisphosphonate), distant recurrence (22.3% and 20.9%, respectively), bone recurrence (8.4% and 6.9%, respectively), or non-bone recurrence (15.1% and 15%, respectively).
Similarly, no significant effect of bisphosphonates was found for local recurrence (6.3% and 5.5%, respectively) or contralateral breast cancer (2.5% and 2.4%, respectively).
Among postmenopausal women, adjuvant bisphosphonates significantly reduced the risk of distant recurrence versus no bisphosphonate: 21.9% versus 18.4% at 10 years (P=.0003, an absolute gain of 3.5%). This difference was mainly driven by the 10-year reduction in bone recurrence: 8.8% versus 5.9% (P<.0001, an absolute gain of 2.9%).
Adjuvant bisphosphonates had no effect on mortality due to breast cancer or other causes in the overall analysis; however, among postmenopausal women, at 10 years there was an absolute gain of 3.1% for breast cancer mortality (18.3% for no bisphosphonate vs 15.2% for bisphosphonate; P=.004); and an absolute gain of 2.3% for all-cause mortality (23.8% for no bisphosphonate vs 21.5% for bisphosphonate; P=.007).
Peter Ravdin, MD, PhD, Cancer Therapy and Research Center, San Antonio, TX, called these results “practice changing.” He said that the impact of bisphosphonates in the adjuvant setting is comparable to that of chemotherapy and trastuzumab in HER2-positive women. Ravdin was not involved in any of the trials included in the meta-analysis.
Breast Cancer Agents in the Pipeline
Below are summaries of some of the newer agents on the horizon the for treatment of patients with breast cancer selected from presentations at the San Antonio Breast Cancer Symposium.
Veliparib, a PARP inhibitor, showed promise in the I-SPY 2 trial for the neoadjuvant treatment of triple-negative breast cancer (TNBC) in combination with carboplatin. This combination will move to phase 3 testing in TNBC. Veliparib is also being studied in advanced breast cancer, cervical cancer, and ovarian cancer. (For further details of I-SPY 2, see article on page 47.)
Ridaforolimus (RIDA), an mTOR inhibitor, is a non-prodrug analogue of rapamycin. Dalotuzumab (DALO) is a monoclonal antibody targeted to insulin-like growth factor 1; the scientific rationale for the combination of RIDA/DALO is upstream and downstream inhibition of molecular targets on the PIK3 pathway. In one phase 2 trial of RIDA/DALO in metastatic estrogen receptor–positive (ER+) breast cancer that progressed on previous treatments, median progression-free survival (PFS) was similar to that of exemestane, but no survival advantage was shown for the combination. The trial was stopped due to the toxicity experienced at the doses used, but the investigators concluded that further study is warranted. Lower doses of RIDA will be studied in the new phase 2 trial for high-proliferation ER+ breast cancer progressing on prior hormonal therapies. The study will compare RIDA/DALO versus RIDA/DALO/exemestane in this group of patients.
Ganetespib, a heat shock protein 90 (Hsp90) inhibitor, is now in phase 2 testing as frontline therapy in women with metastatic HER2-positive (HER2+) or TNBC in the ENCHANT-1 trial. Hsp90 inhibitors block multiple oncogenic pathways that play key roles in different breast cancer subtypes. ENCHANT-1 showed that treatment with ganetespib was well tolerated with an acceptable safety profile; diarrhea is the most common side effect. Ganetespib demonstrated promising antitumor activity in both the HER2+ and TNBC subgroups, with durable responses. Enrollment is continuing in the phase 2 trial. Future strategies that will be studied include combinations with other treatments in early and advanced-stage breast cancer, and biomarker studies will be conducted to try to determine which patients benefit from this treatment.
Palbociclib, an oral selective cyclin-dependent kinase 4/6 inhibitor, passed the phase 2 hurdle and has been given breakthrough status by the FDA. In the phase 2 trial, palbociclib plus letrozole improved PFS versus letrozole alone in advanced/metastatic ER+, HER2+ breast cancer; median PFS was 26.1 months versus 7.5 months with letrozole alone.
Palbociclib is now in phase 3 testing in the PENELOPE trial as adjuvant therapy for patients with hormone receptor–positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy. Following neoadjuvant chemotherapy and surgery with or without radiation therapy, about 800 patients will be randomized to once-daily oral palbociclib versus placebo for 13 cycles. Patients will receive concomitant endocrine therapy according to local standards. They will be followed until progression, secondary malignancy, unacceptable toxicity, or withdrawal of consent.
Ramucirumab, a novel monoclonal angiogenesis inhibitor targeted to VEGFR-2, failed to meet its primary end point of PFS in the ROSE/TRIO-12 trial when added to docetaxel chemotherapy in metastatic breast cancer. These findings are disappointing and would appear to spell the end of antiangiogenesis agents in breast cancer. However, investigators say that they will search for a biomarker to identify subgroups that could benefit from this strategy. Ramucirumab is moving ahead as second-line therapy for gastric cancer; the FDA has granted ramucirumab priority review in this setting.
Entinostat, a novel oral small molecule inhibitor of benzamide histone deacetylase, was shown to extend PFS when added to exemestane versus exemestane alone in postmenopausal women with advanced ER+ breast cancer progressing on a nonsteroidal aromatase inhibitor in the phase 2 ENCORE 301 study; median PFS was 4.28 months for the combination versus 2.27 months for exemestane alone. Entinostat is now being evaluated in phase 3 trials.
I-SPY 2: First Results Based on Biomarkers/Genetic Signatures in Breast Cancer
Veliparip/carboplatin was identified as a worthy combination to move forward in trials of triple- negative breast cancer (TNBC), a subtype of breast cancer with a very poor prognosis.
This combination was a “winner” in the phase 2 I-SPY 2 trial, a series of studies of novel agents/combinations of therapies in biomarker-identified subsets of patients. The trial has a unique adaptive design that allows screening of a series of novel agents in combination with standard neoadjuvant therapy for high-risk breast cancer in small numbers of patients with a particular biomarker/signature.
These first efficacy results of I-SPY 2 showing that veliparip/carboplatin “graduated” in TNBC were presented by Hope Rugo, MD, University of California at San Francisco. I-SPY 2 has also identified neratinib as a “graduate,” but those data aren’t yet available.
“Our goal is to accelerate the process of identifying drugs that are effective for specific breast cancer subtypes and reduce the cost, time, and numbers of patients needed to get effective drugs to market. Today’s report is on 1 of 7 current experimental arms of I-SPY 2,” Rugo told listeners.
The study compares 12 weekly cycles of standard paclitaxel versus 12 weekly cycles of paclitaxel plus novel agent A versus 12 weekly cycles of paclitaxel plus novel agent B. This treatment is followed by doxorubicin-based chemotherapy. Response is determined by pathologic complete response (pCR), defined as no residual invasive cancers in the breast and lymph nodes, and MRI assessment after definitive surgery.
“Adaptive randomization based on the performance of regimens within biomarker subtypes/MammaPrint genetic signatures is the key for enrolling patients. Random probabilities are updated as the study proceeds according to MammaPrint signature, and the threshold for success is based on response for each patient’s tumor based on MRI and pCR assessment over time,” she explained.
The response of each patient informs the randomization assignment for the next patient on study, she continued. Each new patient benefits from the information obtained from the prior patient [with that same signature]. “This allows us to drop an agent that isn’t working,” Rugo explained.
Randomization is assigned based on performance of the experimental regimens within 8 biomarker subtypes (based on HR, HER2, and MammaPrint He-1 and Hi-2).
The results reported here included 71 evaluable patients; 44 had TNBC. The estimated probabilities of pCR showed that the probability of success with velipa- rip/carboplatin is 99%, mainly due to the success of this regimen in TNBC. By contrast, veliparip/carboplatin had little probability of succeeding in the HER2-positive/hormone receptor–positive subset.
The ultimate plan for drugs that “graduate” in I-SPY 2 is a 300-patient phase 3 trial that includes the subset of patients that will benefit from that drug. “The phase 3 trial will incorporate outcome data to correspond with pCR. We hope this will be a mechanism for accelerated approval,” Rugo said.